Updated on 2023/10/10

写真a

 
TSUKAMURA, Hiroko
 
Organization
Graduate School of Bioagricultural Sciences Department of Animal Sciences Professor
Vice President, etc. Director
Graduate School
Graduate School of Bioagricultural Sciences
Undergraduate School
School of Agricultural Sciences
Title
Professor
Contact information
メールアドレス
External link

Degree 2

  1. PhD ( 1991.3   Nagoya University ) 

  2. MSc ( 1988.3   Nagoya University ) 

Research Interests 2

  1. Reproductive Science, Neuroendocrinology, Animal Reproduction, Sexual differentiation of the brain, Inhibition of reproductive function during lactation, suppression of GnRH/lutenizing hormone secretion by suckling stimulus, estrogen positive feedback mechanism regulating GnRH/LH release

  2. 性腺刺激ホルモン

Research Areas 4

  1. Others / Others  / Applied Animal Science

  2. Others / Others  / Basic Veterinary Science/Basic Animal Science

  3. Others / Others  / Livestock Science/Meadow Studies

  4. Environmental Science/Agriculture Science / Environmental agriculture  / Animal Reproduction/Neuroendocrinology

Current Research Project and SDGs 4

  1. Mechanism responsible for sexual differentiation of the brain

  2. メタスチン(キスペプチン)による生殖機能制御機構

  3. Neuroendocrine mechanism for regulation of reproductive function by neutrition

  4. Neuroendocrine mechanism for the stress-induced suppression of gonadotropin secretion

Research History 14

  1. Vice-president of Nagoya Universtiy

    2021.4

  2. Nagoya University   Trustee / Vice President   Director in General

    2015.4

  3. Nagoya University

    2015.4 - 2020.3

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    Country:Japan

  4. Nagoya University   Professor

    2013.3

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    Country:Japan

  5. 名古屋大学大学院生命農学研究科准教授

    2007.4 - 2013.2

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    Country:Japan

  6. Director of Gender Equality Office

    2006.4

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    Country:Japan

  7. Nagoya University   Administrative Support Organizations Gender Equality Office   Head

    2006.4

  8. 名古屋大学男女共同参画担当総長補佐(兼任)

    2006.4 - 2015.3

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    Country:Japan

  9. 大学共同利用機関法人自然科学研究機構基礎生物学研究所客員助教授(併任)

    2004.2 - 2008.3

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    Country:Japan

  10. 名古屋大学大学院生命農学研究科助教授

    1998.4 - 2007.3

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    Country:Japan

  11. 名古屋大学農学部助手

    1991.10 - 1998.3

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    Country:Japan

  12. 米国カンサス大学医学部博士研究員

    1991.4 - 1991.10

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    Country:Japan

  13. 日本学術振興会特別研究員(DC)

    1989.4 - 1991.3

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    Country:Japan

  14. Nagoya University

    1904.1

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Education 5

  1. Nagoya University   Graduate School, Division of Agriculture

    1988.4 - 1991.3

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    Country: Japan

  2. Kansas University Medical Center

    1990.10 - 1991.3

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    Country: United States

  3. Nagoya University   Graduate School, Division of Agriculture

    1986.4 - 1988.3

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    Country: Japan

  4. Nagoya University   Faculty of Agriculture

    1982.4 - 1986.3

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    Country: Japan

  5. Kinjo Gakuin University   Faculty of Home Economics

    1977.4 - 1981.3

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    Country: Japan

Professional Memberships 14

  1. 日本繁殖生物学会   理事長

    2019.8

  2. 日本畜産学会

  3. 日本内分泌学会   理事

    2014.4

  4. 日本生殖内分泌学会   副会長

    2015.4

  5. 日本神経内分泌学会   理事

  6. 日本下垂体研究会   幹事

    2008.4

  7. 日本比較内分泌学会   幹事

    2003.4

  8. Endocrine Society

  9. Society for Neuroscience

  10. International Society of Neuroendocrinology

  11. 神経科学学会

  12. 日本神経科学学会

  13. Society for the Study of Reproduction

  14. 日本生殖内分泌学会

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Committee Memberships 27

  1. あいち男女共同参画財団   理事  

    2006   

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    Committee type:Other

  2. 国立大学協会教育・研究委員会   専門委員  

    2006.4   

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    Committee type:Government

  3. 内閣府男女共同参画局男女共同参画会議基本問題・影響調査専門調査会   専門委員  

    2011   

  4. 名古屋市科学館協議会   委員  

    2011.7   

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    Committee type:Municipal

  5. 日本繁殖生物学会   理事長  

    2020.4   

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    Committee type:Academic society

  6. 文科省大学設置室農学専門委員会   委員  

    2019.4   

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    Committee type:Government

  7. 名古屋市男女平等参画推進会議   会長  

    2018.4   

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    Committee type:Municipal

  8. 刈谷市「日本女性会議2020刈谷」実行委員会   副委員長  

    2018.4   

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    Committee type:Municipal

  9. 農水省獣医審議会   委員  

    2018.4   

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    Committee type:Government

  10. 日本学術会議科学者委員会学協会連携分科会   委員  

    2018.4   

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    Committee type:Government

  11. 大府市行財政改革委員会   委員  

    2017.4   

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    Committee type:Municipal

  12. 日本学術会議   連携会員  

    2017.4   

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    Committee type:Government

  13. 日本学術会議畜産学分科会   委員  

    2017.4   

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    Committee type:Government

  14. 東北大学男女共同参画アドバイザリーボード委員会   委員  

    2016.4   

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    Committee type:Other

  15. 瀬戸市男女共同参画審議会   会長  

    2016.4 - 2018.3   

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    Committee type:Municipal

  16. あいち女性の活躍促進会議   委員  

    2014.1   

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    Committee type:Municipal

  17. 文部科学省 科学技術・学術政策研究所 科学技術動向研究センター   専門調査員  

    2013.4   

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    Committee type:Government

  18. 科学研究費委員会   専門委員  

    2012.10   

  19. 中部日本放送番組審議会   委員  

    2010.4 - 2012.3   

  20. 名古屋市男女平等参画審議会   委員  

    2007.4 - 2011.3   

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    Committee type:Municipal

  21. 日本学術会議   連携会員  

    2006   

  22. 日本学術会議「学術とジェンダー委員会」   委員  

    2006   

  23. 名古屋市地球環境推進部会   副会長  

    2004   

  24. 名古屋市公害防止条例見直し部会   委員  

    2002   

  25. 愛岐処分場専門委員会   委員  

    2001 - 2007   

  26. 科学技術振興調整費イノベーション創出若手養成作業部会   委員  

    2001   

  27. 名古屋市環境審議会   委員  

    1998.8 - 2005.7   

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Awards 5

  1. Women's Challenge Support Award

    2022.6   Cabinet Office in Japan  

  2. 名古屋市教育委員会表彰

    2021.11   名古屋市教育委員会  

  3. Kobayashi award from the Japan Society for Comparative Endocrinology

    2019.11   Japan Society for Comparative Endocrinology   The brain mechanism regulating mammalian reproduction

    Hiroko Tsukamura

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    Award type:International academic award (Japan or overseas)  Country:Japan

  4. 下垂体研究会吉村賞

    2003   下垂体研究会  

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    Country:Japan

  5. 家畜繁殖学会島村賞

    1995   家畜繁殖学会  

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    Country:Japan

 

Papers 251

  1. Enkephalin-δ opioid receptor signaling partly mediates suppression of LH release during early lactation in rats. Reviewed

    Tsuchida, H., Takizawa, M., Nonogaki, M., Inoue, N., Uenoyama, Y., and Tsukamura H.

    Journal of Reproduction and Development   Vol. 69   page: 192 - 197   2023.8

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1262/jrd.2023-006

  2. The impact of inflammatory stress on hypothalamic kisspeptin neurons: Mechanisms underlying inflammation-associated infertility in humans and domestic animals Invited Reviewed

    Fumie Magata, Hiroko Tsukamura, Fuko Matsuda

    Peptides   Vol. 162   page: 170958 - 170958   2023.4

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

    DOI: 10.1016/j.peptides.2023.170958

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    PubMed

  3. Hindbrain Adenosine 5-Triphosphate (ATP)-Purinergic Signaling Triggers LH Surge and Ovulation via Activation of AVPV Kisspeptin Neurons in Rats. Reviewed

    Inoue N, Hazim S, Tsuchida H, Dohi Y, Ishigaki R, Takahashi A, Otsuka Y, Yamada K, Uenoyama Y, Tsukamura H

    The Journal of neuroscience : the official journal of the Society for Neuroscience   Vol. 43 ( 12 ) page: 2140 - 2152   2023.3

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1523/JNEUROSCI.1496-22.2023

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  4. Enkephalin-δ Opioid Receptor Signaling Mediates Glucoprivic Suppression of LH Pulse and Gluconeogenesis in Female Rats. Reviewed

    Tsuchida H, Nonogaki M, Takizawa M, Inoue N, Uenoyama Y, Tsukamura H

    Endocrinology   Vol. 164 ( 3 )   2023.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    DOI: 10.1210/endocr/bqac216

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  5. Intronic Enhancer Is Essential for Nr5a1 Expression in the Pituitary Gonadotrope and for Postnatal Development of Male Reproductive Organs in a Mouse Model. Reviewed International journal

    Yuichi Shima, Kanako Miyabayashi, Takami Mori, Koji Ono, Mizuki Kajimoto, Hae Lim Cho, Hitomi Tsuchida, Yoshihisa Uenoyama, Hiroko Tsukamura, Kentaro Suzuki, Man Ho Choi, Kazunori Toida

    International journal of molecular sciences   Vol. 24 ( 1 )   2023.1

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    Language:English   Publishing type:Research paper (scientific journal)  

    Nuclear receptor subfamily 5 group A member 1 (NR5A1) is expressed in the pituitary gonadotrope and regulates their differentiation. Although several regulatory regions were implicated in Nr5a1 gene expression in the pituitary gland, none of these regions have been verified using mouse models. Furthermore, the molecular functions of NR5A1 in the pituitary gonadotrope have not been fully elucidated. In the present study, we generated mice lacking the pituitary enhancer located in the 6th intron of the Nr5a1 gene. These mice showed pituitary gland-specific disappearance of NR5A1, confirming the functional importance of the enhancer. Enhancer-deleted male mice demonstrated no defects at fetal stages. Meanwhile, androgen production decreased markedly in adult, and postnatal development of reproductive organs, such as the seminal vesicle, prostate, and penis was severely impaired. We further performed transcriptomic analyses of the whole pituitary gland of the enhancer-deleted mice and controls, as well as gonadotropes isolated from Ad4BP-BAC-EGFP mice. These analyses identified several genes showing gonadotrope-specific, NR5A1-dependent expressions, such as Spp1, Tgfbr3l, Grem1, and Nr0b2. These factors are thought to function downstream of NR5A1 and play important roles in reproductive organ development through regulation of pituitary gonadotrope functions.

    DOI: 10.3390/ijms24010192

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  6. Dynorphin-κ-opioid receptor signaling, but not µ-opioid receptor signaling, partly mediates the suppression of luteinizing hormone release during late lactation in rats. Reviewed International journal

    Hitomi Tsuchida, Miku Nonogaki, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Neuroscience letters   Vol. 791   page: 136920 - 136920   2022.11

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

    Follicular development and ovulation are profoundly suppressed during lactation. This suppression is suggested to be due to the suckling-induced inhibition of the kisspeptin gene (the master regulator of reproduction) in the arcuate nucleus (ARC) and subsequent inhibition of pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin release. The present study examined whether hypothalamic κ-opioid receptor (KOR) or µ-opioid receptor (MOR) signaling mediates the suppression of luteinizing hormone (LH) release induced by suckling stimulus during late lactation in rats. Central administration of a selective KOR antagonist blocked the suppression of LH release on Day 16 of lactation; however, central administration of a selective MOR antagonist failed to block the suppression. The suckling stimulus significantly increased the number of fos (a marker for neural activation)-positive Pdyn (dynorphin gene)-expressing cells in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) but not in the ARC. Taken together, these results suggest that central KOR signaling, but not MOR signaling, at least partly, mediates the suppression of LH release induced by suckling stimulus during late lactation, and PVN and SON Dyn neurons may be involved in the suppression in rats.

    DOI: 10.1016/j.neulet.2022.136920

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  7. Intrauterine LPS inhibited arcuate Kiss1 expression, LH pulses, and ovarian function in rats. Reviewed International journal

    Fumie Magata, Lisa Toda, Marimo Sato, Takahiro Sakono, James K Chambers, Kazuyuki Uchida, Hiroko Tsukamura, Fuko Matsuda

    Reproduction (Cambridge, England)   Vol. 164 ( 5 ) page: 207 - 219   2022.11

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    Language:English   Publishing type:Research paper (scientific journal)  

    In brief: Uterine inflammatory diseases are a major cause of infertility in humans and domestic animals. The current findings that intrauterine lipopolysaccharide is absorbed in systemic circulation and attenuates ovarian cyclic activities could provide a basis for developing novel treatments to improve fertility. Abstract: Uterine inflammatory diseases are a major cause of infertility in humans and domestic animals. Circulating lipopolysaccharide (LPS), a bacterial endotoxin causing uterine inflammation, reportedly downregulates the hypothalamic-pituitary-gonadal axis to mediate ovarian dysfunction. In contrast, the mechanism whereby intrauterine LPS affects ovarian function has not been fully clarified. This study aimed to elucidate whether uterine exposure to LPS downregulates hypothalamic kisspeptin gene (Kiss1) expression, gonadotropin release, and ovarian function. Uterine inflammation was induced by intrauterine LPS administration to ovary-intact and ovariectomized female rats. As a result, plasma LPS concentrations were substantially higher in control rats until 48 h post injection, and the estrous cyclicity was disrupted with a prolonged diestrous phase. Three days post injection, the number of Graafian follicles and plasma estradiol concentration were reduced in LPS-treated rats, while numbers of Kiss1-expressing cells in the anteroventral periventricular nucleus and arcuate nucleus (ARC) were comparable in ovary-intact rats. Four days post injection, ovulation rate and plasma progesterone levels reduced significantly while gene expression of interleukin1β and tumor necrosis factor α was upregulated in the ovaries of LPS-treated rats that failed to ovulate. Furthermore, the number of Kiss1-expressing cells in the ARC and pulsatile luteinizing hormone (LH) release were significantly reduced in ovariectomized rats 24 h post injection. In conclusion, these results indicate that intrauterine LPS is absorbed in systemic circulation and attenuates ovarian function. This detrimental effect might be caused, at least partly, by the inhibition of ARC Kiss1 expression and LH pulses along with an induction of ovarian inflammatory response.

    DOI: 10.1530/REP-22-0047

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  8. Establishment of embryo transfer in the musk shrew (Suncus murinus). Reviewed

    Naoko Inoue, Akinori Hotta, Teppei Goto, Masumi Hirabayashi, Yoshihisa Uenoyama, Hiroko Tsukamura

    The Journal of reproduction and development   Vol. 68 ( 5 ) page: 340 - 344   2022.10

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    The present study established techniques to induce pseudopregnancy, in vitro oocyte cultures from pronuclear to 2- to 4-cell stages, and embryo transfer in musk shrews, a reflex ovulator. Offspring were subsequently obtained by transferring in vivo-developed or in vitro-cultured embryos. Female musk shrews received human chronic gonadotropin (hCG), with or without mating stimuli, from vasectomized males to produce pseudopregnant recipients. Embryos at the 2- to 4-cell stage were collected 44-48 h after mating. Another set of embryos was collected 26-27 h after mating and then cultured for 20 h from the pronuclear to 2- to 4-cell stages. Subsequently, embryos were transferred into the oviducts of pseudopregnant recipients 24 or 48 h after the induction of pseudopregnancy. Offsprings were successfully obtained from recipients that received hCG 24 h before embryo transfer, regardless of mating stimuli. These techniques may be valuable for producing transgenic musk shrews.

    DOI: 10.1262/jrd.2022-003

    PubMed

  9. Opioidergic pathways and kisspeptin in the regulation of female reproduction in mammals. Invited Reviewed International journal

    Yoshihisa Uenoyama, Hitomi Tsuchida, Mayuko Nagae, Naoko Inoue, Hiroko Tsukamura

    Frontiers in neuroscience   Vol. 16   page: 958377 - 958377   2022.8

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

    Endogenous opioid peptides have attracted attention as critical neuropeptides in the central mechanism regulating female reproduction ever since the discovery that arcuate dynorphin neurons that coexpress kisspeptin and neurokinin B (NKB), which are also known as kisspeptin/neurokinin B/dynorphin (KNDy) neurons, play a role as a master regulator of pulsatile gonadotropin-releasing hormone (GnRH) release in mammals. In this study, we first focus on the role of dynorphin released by KNDy neurons in the GnRH pulse generation. Second, we provide a historical overview of studies on endogenous opioid peptides. Third, we discuss how endogenous opioid peptides modulate tonic GnRH/gonadotropin release in female mammals as a mediator of inhibitory internal and external cues, such as ovarian steroids, nutritional status, or stress, on reproduction. Then, we discuss the role of endogenous opioid peptides in GnRH surge generation in female mammals.

    DOI: 10.3389/fnins.2022.958377

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  10. Generation of Tfap2c-T2A-tdTomato knock-in reporter rats via adeno-associated virus-mediated efficient gene targeting Reviewed

    Oikawa Mami, Nagae Mayuko, Mizuno Naoaki, Iwatsuki Kenyu, Yoshida Fumika, Inoue Naoko, Uenoyama Yoshihisa, Tsukamura Hiroko, Nakauchi Hiromitsu, Hirabayashi Masumi, Kobayashi Toshihiro

    MOLECULAR REPRODUCTION AND DEVELOPMENT   Vol. 89 ( 3 ) page: 129 - 132   2022.3

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1002/mrd.23562

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  11. Kiss1-dependent and independent release of luteinizing hormone and testosterone in perinatal male rats Reviewed

    Chen Jing, Minabe Shiori, Munetomo Arisa, Magata Fumie, Sato Marimo, Nakamura Sho, Hirabayashi Masumi, Ishihara Yasuhiro, Yamazaki Takeshi, Uenoyama Yoshihisa, Tsukamura Hiroko, Matsuda Fuko

    ENDOCRINE JOURNAL     2022.2

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    Language:Japanese   Publishing type:Research paper (scientific journal)  

    DOI: 10.1507/endocrj.EJ21-0620

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  12. Kobayashi Award 2019: The neuroendocrine regulation of the mammalian reproduction. Invited Reviewed International journal

    Hiroko Tsukamura

    General and comparative endocrinology   Vol. 315   page: 113755 - 113755   2022.1

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

    Mammalian reproductive function is a complex system of many players orchestrated by the hypothalamus-pituitary-gonadal (HPG) axis. The hypothalamic gonadotropin-releasing hormone (GnRH) and the consequent pituitary gonadotropin release show two modes of secretory patterns, namely the surge and pulse modes. The surge mode is triggered by the positive feedback action of estrogen secreted from the mature ovarian follicle to induce ovulation in females of most mammalian species. The pulse mode of GnRH release is required for stimulating tonic gonadotropin secretion to drive folliculogenesis, spermatogenesis and steroidogenesis and is negatively fine-tuned by the sex steroids. Accumulating evidence suggests that hypothalamic kisspeptin neurons are the master regulator for animal reproduction to govern the HPG axis. Specifically, kisspeptin neurons located in the anterior hypothalamus, such as the anteroventral periventricular nucleus (AVPV) in rodents and preoptic nucleus (POA) in ruminants, primates and others, and the neurons located in the arcuate nucleus (ARC) in posterior hypothalamus in most mammals are considered to play a key role in generating the surge and pulse modes of GnRH release, respectively. The present article focuses on the role of AVPV (or POA) kisspeptin neurons as a center for GnRH surge generation and of the ARC kisspeptin neurons as a center for GnRH pulse generation to mediate estrogen positive and negative feedback mechanisms, respectively, and discusses how the estrogen epigenetically regulates kisspeptin gene expression in these two populations of neurons. This article also provides the mechanism how malnutrition and lactation suppress GnRH/gonadotropin pulses through an inhibition of the ARC kisspeptin neurons. Further, the article discusses the programming effect of estrogen on kisspeptin neurons in the developmental brain to uncover the mechanism underlying the sex difference in GnRH/gonadotropin release as well as an irreversible infertility induced by supra-physiological estrogen exposure in rodent models.

    DOI: 10.1016/j.ygcen.2021.113755

    PubMed

  13. Cellular and molecular mechanisms regulating the KNDy neuronal activities to generate and modulate GnRH pulse in mammals. Invited Reviewed International journal

    Kana Ikegami, Youki Watanabe, Sho Nakamura, Teppei Goto, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Frontiers in neuroendocrinology   Vol. 64   page: 100968 - 100968   2022.1

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    Authorship:Last author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    Accumulating findings during the past decades have demonstrated that the hypothalamic arcuate kisspeptin neurons are supposed to be responsible for pulsatile release of gonadotropin-releasing hormone (GnRH) to regulate gametogenesis and steroidogenesis in mammals. The arcuate kisspeptin neurons express neurokinin B (NKB) and dynorphin A (Dyn), thus, the neurons are also referred to as KNDy neurons. In the present article, we mainly focus on the cellular and molecular mechanisms underlying GnRH pulse generation, that is focused on the action of NKB and Dyn and an interaction between KNDy neurons and astrocytes to control GnRH pulse generation. Then, we also discuss the factors that modulate the activity of KNDy neurons and consequent pulsatile GnRH/LH release in mammals.

    DOI: 10.1016/j.yfrne.2021.100968

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  14. Kisspeptin neurons as a key player bridging the endocrine system and sexual behavior in mammals. Invited Reviewed International journal

    Sho Nakamura, Youki Watanabe, Teppei Goto, Kana Ikegami, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Frontiers in neuroendocrinology   Vol. 64   page: 100952 - 100952   2022.1

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    Authorship:Last author, Corresponding author   Language:Japanese   Publishing type:Research paper (scientific journal)  

    Reproductive behaviors are sexually differentiated: for example, male rodents show mounting behavior, while females in estrus show lordosis behavior as sex-specific sexual behaviors. Kisspeptin neurons govern reproductive function via direct stimulation of gonadotropin-releasing hormone (GnRH) and subsequent gonadotropin release for gonadal steroidogenesis in mammals. First, we discuss the role of hypothalamic kisspeptin neurons as an indispensable regulator of sexual behavior by stimulating the synthesis of gonadal steroids, which exert "activational effects" on the behavior in adulthood. Second, we discuss the central role of kisspeptin neurons that are directly involved in neural circuits controlling sexual behavior in adulthood. We then focused on the role of perinatal hypothalamic kisspeptin neurons in the induction of perinatal testosterone secretion for its "organizational effects" on masculinization/defeminization of the male brain in rodents during a critical period. We subsequently concluded that kisspeptin neurons are key players in bridging the endocrine system and sexual behavior in mammals.

    DOI: 10.1016/j.yfrne.2021.100952

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  15. Central somatostatin-somatostatin receptor 2 signaling mediates lactational suppression of luteinizing hormone release via the inhibition of glutamatergic interneurons during late lactation in rats. Reviewed

    Arisa Sugimoto, Hitomi Tsuchida, Mayuko Nagae, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    The Journal of reproduction and development   Vol. 68 ( 3 ) page: 190 - 197   2022

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

    Reproductive function is suppressed during lactation owing to the suckling-induced suppression of the kisspeptin gene (Kiss1) expression in the arcuate nucleus (ARC) and subsequent suppression of luteinizing hormone (LH) release. Our previous study revealed that somatostatin (SST) neurons mediate suckling-induced suppression of LH release via SST receptor 2 (SSTR2) in ovariectomized lactating rats during early lactation. This study examined whether central SST-SSTR2 signaling mediates the inhibition of ARC Kiss1 expression and LH release in lactating rats during late lactation and whether the inhibition of glutamatergic neurons, stimulators of LH release, is involved in the suppression of LH release mediated by central SST-SSTR2 signaling in lactating rats. A central injection of the SSTR2 antagonist CYN154806 (CYN) significantly increased ARC Kiss1 expression in lactating rats on day 16 of lactation. Dual in situ hybridization revealed that few ARC Kiss1-positive cells co-expressed Sstr2, and some of the ARC Slc17a6 (a glutamatergic neuronal marker)-positive cells co-expressed Sstr2. Furthermore, almost all ARC Kiss1-positive cells co-expressed Grin1, a subunit of N-methyl-D-aspartate (NMDA) receptors. The numbers of Slc17a6/Sstr2 double-labeled and Slc17a6 single-labeled cells were significantly lower in lactating dams than in non-lactating rats whose pups had been removed after parturition. A central injection of an NMDA antagonist reversed the CYN-induced increase in LH release in lactating rats. Overall, these results suggest that central SST-SSTR2 signaling, at least partly, mediates the suppression of ARC Kiss1 expression and LH release by inhibiting ARC glutamatergic interneurons in lactating rats.

    DOI: 10.1262/jrd.2022-009

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  16. <i>Kiss</i>1-dependent and independent release of luteinizing hormone and testosterone in perinatal male rats Reviewed

    Chen Jing, Minabe Shiori, Munetomo Arisa, Magata Fumie, Sato Marimo, Nakamura Sho, Hirabayashi Masumi, Ishihara Yasuhiro, Yamazaki Takeshi, Uenoyama Yoshihisa, Tsukamura Hiroko, Matsuda Fuko

    ENDOCRINE JOURNAL   Vol. 69 ( 7 ) page: 797 - 807   2022

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  17. Central µ-Opioid Receptor Antagonism Blocks Glucoprivic LH Pulse Suppression and Gluconeogenesis/Feeding in Female Rats. Reviewed International journal

    Hitomi Tsuchida, Narumi Kawai, Koki Yamada, Marina Takizawa, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Endocrinology   Vol. 162 ( 10 )   2021.10

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    Energetic status often affects reproductive function, glucose homeostasis, and feeding in mammals. Malnutrition suppresses pulsatile release of the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) and increases gluconeogenesis and feeding. The present study aims to examine whether β-endorphin-μ-opioid receptor (MOR) signaling mediates the suppression of pulsatile GnRH/LH release and an increase in gluconeogenesis/feeding induced by malnutrition. Ovariectomized female rats treated with a negative feedback level of estradiol-17β (OVX + low E2) receiving 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, intravenously (iv) were used as a malnutrition model. An administration of D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), a selective MOR antagonist, into the third ventricle blocked the suppression of the LH pulse and increase in gluconeogenesis/feeding induced by iv 2DG administration. Histological analysis revealed that arcuate Kiss1 (kisspeptin gene)-expressing cells and preoptic Gnrh1 (GnRH gene)-expressing cells co-expressed little Oprm1 (MOR gene), while around 10% of arcuate Slc17a6 (glutamatergic marker gene)-expressing cells co-expressed Oprm1. Further, the CTOP treatment decreased the number of fos-positive cells in the paraventricular nucleus (PVN) in OVX + low E2 rats treated with iv 2DG but failed to affect the number of arcuate fos-expressing Slc17a6-positive cells. Taken together, these results suggest that the central β-endorphin-MOR signaling mediates the suppression of pulsatile LH release and that the β-endorphin may indirectly suppress the arcuate kisspeptin neurons, a master regulator for GnRH/LH pulses during malnutrition. Furthermore, the current study suggests that central β-endorphin-MOR signaling is also involved in gluconeogenesis and an increase in food intake by directly or indirectly acting on the PVN neurons during malnutrition in female rats.

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  18. Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction Reviewed

    Uenoyama Yoshihisa, Nagae Mayuko, Tsuchida Hitomi, Inoue Naoko, Tsukamura Hiroko

    FRONTIERS IN ENDOCRINOLOGY   Vol. 12   2021.9

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    DOI: 10.1152/ajplegacy.1931.97.2.291

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  19. Kisspeptin Neurons and Estrogen-Estrogen Receptor α Signaling: Unraveling the Mystery of Steroid Feedback System Regulating Mammalian Reproduction. Invited Reviewed International journal

    Yoshihisa Uenoyama, Naoko Inoue, Sho Nakamura, Hiroko Tsukamura

    International journal of molecular sciences   Vol. 22 ( 17 )   2021.9

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    Estrogen produced by ovarian follicles plays a key role in the central mechanisms controlling reproduction via regulation of gonadotropin-releasing hormone (GnRH) release by its negative and positive feedback actions in female mammals. It has been well accepted that estrogen receptor α (ERα) mediates both estrogen feedback actions, but precise targets had remained as a mystery for decades. Ever since the discovery of kisspeptin neurons as afferent ERα-expressing neurons to govern GnRH neurons, the mechanisms mediating estrogen feedback are gradually being unraveled. The present article overviews the role of kisspeptin neurons in the arcuate nucleus (ARC), which are considered to drive pulsatile GnRH/gonadotropin release and folliculogenesis, in mediating the estrogen negative feedback action, and the role of kisspeptin neurons located in the anteroventral periventricular nucleus-periventricular nucleus (AVPV-PeN), which are thought to drive GnRH/luteinizing hormone (LH) surge and consequent ovulation, in mediating the estrogen positive feedback action. This implication has been confirmed by the studies showing that estrogen-bound ERα down- and up-regulates kisspeptin gene (Kiss1) expression in the ARC and AVPV-PeN kisspeptin neurons, respectively. The article also provides the molecular and epigenetic mechanisms regulating Kiss1 expression in kisspeptin neurons by estrogen. Further, afferent ERα-expressing neurons that may regulate kisspeptin release are discussed.

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  20. Morphological Analysis of the Hindbrain Glucose Sensor-Hypothalamic Neural Pathway Activated by Hindbrain Glucoprivation. Reviewed International journal

    Marimo Sato, Shiori Minabe, Takahiro Sakono, Fumie Magata, Sho Nakamura, Youki Watanabe, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Fuko Matsuda

    Endocrinology   Vol. 162 ( 9 )   2021.9

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    Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 hour induced messenger RNA (mRNA) expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 hour significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine β-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.

    DOI: 10.1210/endocr/bqab125

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  21. Reduction of arcuate kappa-opioid receptor-expressing cells increased luteinizing hormone pulse frequency in female rats. Reviewed

    Mingdao Dai, Sho Nakamura, Chudai Takahashi, Marimo Sato, Arisa Munetomo, Fumie Magata, Yoshihisa Uenoyama, Hiroko Tsukamura, Fuko Matsuda

    Endocrine journal   Vol. 68 ( 8 ) page: 933 - 941   2021.8

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    The brain mechanism responsible for the pulsatile secretion of gonadotropin-releasing hormone (GnRH) is important for maintaining reproductive function in mammals. Accumulating evidence suggests that kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in the hypothalamic arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH and subsequent gonadotropin secretion. Dynorphin A (Dyn) and its receptor, kappa-opioid receptor (KOR, encoded by Oprk1), have been shown to be involved in the suppression of pulsatile GnRH/luteinizing hormone (LH) release. On the other hand, it is still unclear whether the inhibitory Dyn signaling affects KNDy neurons or KOR-expressing non-KNDy cells in the ARC or other brain regions. We therefore aimed to clarify the role of ARC-specific Dyn-KOR signaling in the regulation of pulsatile GnRH/LH release by the ARC specific cell deletion of KOR-expressing cells using Dyn-conjugated-saporin (Dyn-SAP). Estrogen-primed ovariectomized female rats were administered Dyn-SAP to the ARC. In situ hybridization of Oprk1 showed that ARC Dyn-SAP administration significantly decreased the number of Oprk1-expressing cells in the ARC, but not in the ventromedial hypothalamic nucleus and paraventricular nucleus. The frequency of LH pulses significantly increased in animals bearing the ARC Dyn-SAP administration. The number of Kiss1-expressing cells in the ARC was not affected by ARC Dyn-SAP treatment. Dyn-KOR signaling within the ARC seems to mediate the suppression of the frequency of pulsatile GnRH/LH release, and ARC non-KNDy KOR neurons may be involved in the mechanism modulating GnRH/LH pulse generation.

    DOI: 10.1507/endocrj.EJ20-0832

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  22. Effect of diet-induced obesity on kisspeptin-neurokinin B-dynorphin A neurons in the arcuate nucleus and luteinizing hormone secretion in sex hormone-primed male and female rats. Reviewed International journal

    Shiori Minabe, Kinuyo Iwata, Hitomi Tsuchida, Hiroko Tsukamura, Hitoshi Ozawa

    Peptides   Vol. 142   page: 170546 - 170546   2021.8

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    Metabolic stress resulting from either lack or excess of nutrients often causes infertility in both sexes. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) has been suggested to be a key players in reproduction via direct stimulation of the pulsatile gonadotropin-releasing hormone (GnRH) and subsequent gonadotropin release in mammalian species. In this study, we investigated the effect of high-fat diet (HFD) on hypothalamic KNDy gene expression to examine the pathogenic mechanism underlying obesity-induced infertility in male and female rats. Male and female rats at 7 weeks of age were fed with either a standard or HFD for 4 months. In the male rats, the HFD caused a significant suppression of ARC Kiss1 and Pdyn gene expressions, but did not affect the plasma luteinizing hormone (LH) levels and sizes of the morphology of the testis and epididymis. In the female rats, 58% of the HFD-fed female rats exhibited irregular estrous cycles, whereas the remaining rats showed regular cycles. Two of the 10 rats that showed HFD-induced irregular estrous cycles showed profound suppression of LH pulse frequency and the number of ARC Kiss1-expressing cells, whereas the other females showed normal LH pulses and ARC Kiss1 expression. Our finding shows that suppression of ARC Kiss1 expression might be the initial pathological change of hypogonadotropic hypogonadism in HFD-fed male rats, while the obese-related infertility in the female rats may be mainly induced by KNDy-independent pathways. Taken together, ARC kisspeptin neurons in male rats may be susceptible to HFD-induced obesity compared with those in female rats.

    DOI: 10.1016/j.peptides.2021.170546

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  23. Testosterone regulation on quiescin sulfhydryl oxidase 2 synthesis in the epididymis. Reviewed International journal

    Tse-En Wang, Shiori Minabe, Fuko Matsuda, Sheng-Hsiang Li, Hiroko Tsukamura, Kei-Ichiro Maeda, Lee Smith, Laura O'Hara, Bart M Gadella, Pei-Shiue Tsai

    Reproduction (Cambridge, England)   Vol. 161 ( 5 ) page: 593 - 602   2021.5

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    The epididymis is an androgen-responsive organ, whose structure and functions are modulated by the coordination between androgen and epididymal cues. Highly regulated molecular interaction within the epididymis is required to support viable sperm development necessary for subsequent fertilization. In the present study, we extended our earlier findings on a promising epididymal protein, quiescin sulfhydryl oxidase 2 (QSOX2), and demonstrated a positive correlation between testosterone and QSOX2 protein synthesis through the use of loss- and restore-of-function animal models. Moreover, based on transcriptomic analyses and 2D culture system, we determined that an additional polarized effect of glutamate is indispensable for the regulatory action of testosterone on QSOX2 synthesis. In conclusion, we propose noncanonical testosterone signaling supports epididymal QSOX2 protein synthesis, providing a novel perspective on the regulation of sperm maturation within the epididymis.

    DOI: 10.1530/REP-20-0629

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  24. The neuroendocrine regulation of the mammalian reproduction. Invited Reviewed

    Tsukamura, H.

     General and Comparative Endocrinology     2021.3

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  25. Estrogen increases KISS1 expression in newly generated immortalized KISS1-expressing cell line derived from goat preoptic area. Reviewed

    Yukina Oshimo, Arisa Munetomo, Fumie Magata, Yuta Suetomi, Shuhei Sonoda, Yukari Takeuchi, Hiroko Tsukamura, Satoshi Ohkura, Fuko Matsuda

    The Journal of reproduction and development   Vol. 67 ( 1 ) page: 15 - 23   2021.2

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    Kisspeptin neurons located in the hypothalamic preoptic area (POA) are suggested to be responsible for the induction of the gonadotropin-releasing hormone (GnRH) surge and the following luteinizing hormone (LH) surge to regulate female mammals' ovulation. Accumulating evidence demonstrates that the preovulatory level of estrogen activates the POA kisspeptin neurons (estrogen positive feedback), which in turn induces a GnRH/LH surge. This study aimed to derive a cell line from goat POA kisspeptin neurons as an in vitro model to analyze the estrogen positive feedback mechanism in ruminants. Neuron-derived cell clones obtained by the immortalization of POA tissue from a female Shiba goat fetus were analyzed for the expression of kisspeptin (KISS1) and estrogen receptor α (ESR1) genes using quantitative real-time reverse transcription-polymerase chain reaction and three cell clones were selected as POA kisspeptin neuron cell line candidates. One cell line (GP64) out of the three clones showed significant increase in the KISS1 level by incubation with estradiol for 24 h, indicating that the GP64 cells mimic endogenous goat POA kisspeptin neurons. The GP64 cells showed immunoreactivities for kisspeptin and estrogen receptor α and retained a stable growth rate throughout three passages. Further, intracellular calcium levels in the GP64 cells were increased by the KCl challenge, indicating their neurosecretory ability. In conclusion, we generated a new KISS1-expressing cell line derived from goat POA. The current GP64 cell line could be a useful model to elucidate the estrogen positive feedback mechanism responsible for the GnRH/LH surge generation in ruminants.

    DOI: 10.1262/jrd.2020-053

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  26. Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator. Reviewed International journal

    Mayuko Nagae, Yoshihisa Uenoyama, Saki Okamoto, Hitomi Tsuchida, Kana Ikegami, Teppei Goto, Sutisa Majarune, Sho Nakamura, Makoto Sanbo, Masumi Hirabayashi, Kenta Kobayashi, Naoko Inoue, Hiroko Tsukamura

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 118 ( 5 )   2021.2

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    The gonadotropin-releasing hormone (GnRH) pulse is fundamental for mammalian reproduction: GnRH pulse regimens are needed as therapies for infertile women as continuous GnRH treatment paradoxically inhibits gonadotropin release. Circumstantial evidence suggests that the hypothalamic arcuate KNDy neurons expressing kisspeptin (encoded by Kiss1), neurokinin B (encoded by Tac3), and dynorphin A serve as a GnRH pulse generator; however, no direct evidence is currently available. Here, we show that rescuing >20% KNDy neurons by transfecting Kiss1 inside arcuate Tac3 neurons, but not outside of these neurons, recovered folliculogenesis and luteinizing hormone (LH) pulses, an indicator of GnRH pulses, in female global Kiss1 knockout (KO) rats and that >90% conditional arcuate Kiss1 KO in newly generated Kiss1-floxed rats completely suppressed LH pulses. These results first provide direct evidence that KNDy neurons are the GnRH pulse generator, and at least 20% of KNDy neurons are sufficient to maintain folliculogenesis via generating GnRH/gonadotropin pulses.

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  27. Reduction of arcuate kappa-opioid receptor-expressing cells increased luteinizing hormone pulse frequency in female rats Reviewed

    Dai Mingdao, Nakamura Sho, Takahashi Chudai, Sato Marimo, Munetomo Arisa, Magata Fumie, Uenoyama Yoshihisa, Tsukamura Hiroko, Matsuda Fuko

    ENDOCRINE JOURNAL   Vol. 68 ( 8 ) page: 933 - 941   2021

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  28. Role of KNDy Neurons Expressing Kisspeptin, Neurokinin B, and Dynorphin A as a GnRH Pulse Generator Controlling Mammalian Reproduction. Invited Reviewed International journal

    Yoshihisa Uenoyama, Mayuko Nagae, Hitomi Tsuchida, Naoko Inoue, Hiroko Tsukamura

    Frontiers in endocrinology   Vol. 12   page: 724632 - 724632   2021

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    Increasing evidence accumulated during the past two decades has demonstrated that the then-novel kisspeptin, which was discovered in 2001, the known neuropeptides neurokinin B and dynorphin A, which were discovered in 1983 and 1979, respectively, and their G-protein-coupled receptors, serve as key molecules that control reproduction in mammals. The present review provides a brief historical background and a summary of our recent understanding of the roles of hypothalamic neurons expressing kisspeptin, neurokinin B, and dynorphin A, referred to as KNDy neurons, in the central mechanism underlying gonadotropin-releasing hormone (GnRH) pulse generation and subsequent tonic gonadotropin release that controls mammalian reproduction.

    DOI: 10.3389/fendo.2021.724632

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  29. Mating-induced increase in Kiss1 mRNA expression in the anteroventral periventricular nucleus prior to an increase in LH and testosterone release in male rats. Reviewed

    Youki Watanabe, Kana Ikegami, Sho Nakamura, Yoshihisa Uenoyama, Hitoshi Ozawa, Kei-Ichiro Maeda, Hiroko Tsukamura, Naoko Inoue

    The Journal of reproduction and development   Vol. 66 ( 6 ) page: 579 - 586   2020.12

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    Kisspeptin has an indispensable role in gonadotropin-releasing hormone/gonadotropin secretion in mammals. In rodents, kisspeptin neurons are located in distinct brain regions, namely the anteroventral periventricular nucleus-periventricular nucleus continuum (AVPV/PeN), arcuate nucleus (ARC), and medial amygdala (MeA). Among them, the physiological role of AVPV/PeN kisspeptin neurons in males has not been clarified yet. The present study aims to investigate the acute effects of the olfactory and/or mating stimulus with a female rat on hypothalamic and MeA Kiss1 mRNA expression, plasma luteinizing hormone (LH) and testosterone levels in male rats. Intact male rats were exposed to the following stimuli: exposure to clean bedding; exposure to female-soiled bedding as a female-olfactory stimulus; exposure to female-soiled bedding and mating stimulus with a female rat. The mating stimulus significantly increased the number of the AVPV/PeN Kiss1 mRNA-expressing cells in males within 5 minutes after the exposure, and significantly increased LH and testosterone levels, followed by an increase in male sexual behavior. Whereas, the males exposed to female-soiled bedding showed a moderate increase in LH levels and no significant change in testosterone levels and the number of the AVPV/PeN Kiss1 mRNA-expressing cells. Importantly, none of the stimuli affected the number of Kiss1 mRNA-expressing cells in the ARC and MeA. These results suggest that the mating-induced increase in AVPV/PeN Kiss1 mRNA expression may be, at least partly, involved in stimulating LH and testosterone release, and might consequently ensure male mating behavior. This study would be the first report suggesting that the AVPV/PeN kisspeptin neurons in males may play a physiological role in ensuring male reproductive performance.

    DOI: 10.1262/jrd.2020-067

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  30. Seasonal changes in the reproductive performance in local cows receiving artificial insemination in the Pursat province of Cambodia. Reviewed International journal

    Bengthay Tep, Yasuhiro Morita, Shuichi Matsuyama, Satoshi Ohkura, Naoko Inoue, Hiroko Tsukamura, Yoshihisa Uenoyama, Vutha Pheng

    Asian-Australasian journal of animal sciences   Vol. 33 ( 12 ) page: 1922 - 1929   2020.12

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    Objective: The present study aimed to survey seasonal changes in reproductive performance in local cows receiving artificial insemination (AI) in the Pursat province of Cambodia, a tropical country, to investigate if ambient conditions affect the reproductive performance of cows as to better understand the major problems regarding cattle production. Methods: The number of cows receiving AI, resultant number of calving and calving rate were analyzed for those receiving the first AI from 2016 to 2017. The year was divided into three seasons: cool/dry (from November to February), hot/dry (from March to June), and wet (from July to October), based on the maximal temperature and rainfall in Pursat, to analyze the relationship between ambient conditions and the reproductive performance of cows. Body condition scores (BCS) and feeding schemes were also analyzed in these seasons. Results: The number of cows receiving AI was significantly higher in the cool/dry season than the wet season. The number of calving and calving rate were significantly higher in cows receiving AI in the cool/dry season compared with the hot/dry and wet seasons. The cows showed higher BCSs in the cool/dry season compared to the hot/dry and wet seasons probably due to the seasonal changes in the feeding schemes: These cows grazed on wild grasses in the cool/dry season but fed with a limited amount of grasses and straw in the hot/dry and wet seasons. Conclusion: The present study suggests that the low number of cows receiving AI, low number of calving and low calving rate could be mainly due to poor body condition as a result of the poor feeding schemes during the hot/dry and wet seasons. The improvement of body condition by the refinement of feeding schemes may contribute to an increase in the reproductive performance in cows during the hot/dry and wet seasons in Cambodia.

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  31. Paraventricular dynorphin A neurons mediate LH pulse suppression induced by hindbrain glucoprivation in female rats. Reviewed International journal

    Hitomi Tsuchida, Parvin Mostari, Koki Yamada, Sae Miyazaki, Yuki Enomoto, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Endocrinology   Vol. 161 ( 11 )   2020.11

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    Malnutrition suppresses reproductive function in mammals, which is considered to be mostly due to the inhibition of pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin secretion. Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC) play a critical role in the regulation of pulsatile GnRH/gonadotropin release. The present study aimed to examine if the hypothalamic dynorphin A (Dyn) neurons mediate the suppression of GnRH/luteinizing hormone (LH) pulses during malnutrition. Ovariectomized rats treated with a negative feedback level of estradiol-17β-treated (OVX+E2) were administered with peripheral (iv) or fourth cerebroventricle (4V) 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, to serve as a malnutrition model. Central administration of a Dyn receptor antagonist blocked the iv- or 4V-2DG-induced suppression of LH pulses in OVX+E2 rats. The 4V 2DG administration significantly increased the number of Pdyn (Dyn gene)-positive cells co-expressing fos in the paraventricular nucleus (PVN), but not in the ARC and supraoptic nucleus (SON), and the iv 2DG treatment significantly increased the number of fos- and Pdyn-co-expressing cells in the PVN and SON, but decreased it in the ARC. The E2 treatment significantly increased Pdyn expression in the PVN, but not in the ARC and SON. Double in situ hybridization for Kiss1 (kisspeptin gene) and Oprk1 (Dyn receptor gene) revealed that around 60% of ARC Kiss1-expressing cells co-expressed Oprk1. These results suggest that the PVN Dyn neurons, at least in part, mediate LH pulse suppression induced by the hindbrain or peripheral glucoprivation, and Dyn neurons may directly suppress the ARC kisspeptin neurons in female rats.

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  32. Facilitatory and inhibitory role of central amylin administration in the regulation of the gonadotropin-releasing hormone pulse generator activity in goats Reviewed International journal

    Yuri Kitagawa, Takuya Sasaki, Reika Suzumura, Ai Morishima, Ryoki Tatebayashi, Assadullah, Nahoko Ieda, Yasuhiro Morita, Shuichi Matsuyama, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Satoshi Ohkura

    Neuroscience Letters   Vol. 736   page: 135276 - 135276   2020.9

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    © 2020 Elsevier B.V. Pulsatile gonadotropin-releasing hormone (GnRH) secretion is essential for regulating reproductive functions in mammals. GnRH pulses are governed by a neural mechanism that is termed the GnRH pulse generator. In the present study, we investigated the role of central calcitonin receptor (CTR) signaling in the regulation of the GnRH pulse generator activity in ovariectomized goats by administering amylin, an endogenous ligand for CTR, into the lateral ventricle. GnRH pulse generator activity was measured using multiple unit activity (MUA) recordings in the mediobasal hypothalamus. We analyzed changes in the interval of characteristic increases in MUA (MUA volleys). The MUA volley interval shortened immediately after amylin administration, followed by prolonged intervals. Double in situ hybridization for KISS1 (kisspeptin gene) and CALCR (CTR gene) revealed that low expression levels of CALCR were found in the arcuate kisspeptin neurons, which is suggested as the main population of neurons, involved in GnRH pulse generator activity. These results suggest that central amylin-CTR signaling has a biphasic role in the regulation of GnRH pulse generator activity by acting on cells other than the arcuate kisspeptin neurons in goats.

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  33. Testosterone Supplementation Rescues Spermatogenesis and In Vitro Fertilizing Ability of Sperm in Kiss1 Knockout Mice Reviewed International journal

    Teppei Goto, Masumi Hirabayashi, Youki Watanabe, Makoto Sanbo, Koichi Tomita, Naoko Inoue, Hiroko Tsukamura, Yoshihisa Uenoyama

    Endocrinology   Vol. 161 ( 9 )   2020.9

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    © Endocrine Society 2020. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Restoration of spermatogenesis and fertility is a major issue to be solved in male mammals with hypogonadotropic hypogonadism. Kiss1 knockout (KO) male mice are postulated to be a suitable animal model to investigate if hormonal replacement rescues spermatogenesis in mammals with this severe reproductive hormone deficiency, because KO mice replicate the hypothalamic disorder causing hypogonadism. The present study investigated whether testosterone supplementation was able to restore spermatogenesis and in vitro fertilization ability in Kiss1 KO mice. To this end, spermatogenesis, in vitro fertilization ability of Kiss1 KO sperm, and preimplantation development of wild-type embryos inseminated with Kiss1 KO sperm, were examined. The newly generated Kiss1 KO male mice showed infertility with cryptorchidism. Subcutaneous testosterone supplementation for 6 weeks restored plasma and intratesticular testosterone levels, elicited testicular descent, and induced complete spermatogenesis from spermatocytes to elongated spermatids in the testis, resulting in an increase in epididymal sperm number in testosterone-supplemented Kiss1 KO male mice. Epididymal sperm derived from the testosterone-supplemented Kiss1 KO mice showed normal in vitro fertilization ability, and the fertilized eggs showed normal preimplantation development, while the males failed to impregnate females. These results suggest that the failure of spermatogenesis in Kiss1 KO mice is mainly due to a lack of testosterone production, and that Kiss1 KO sperm are capable of fertilizing eggs if the animals receive the appropriate testosterone supplementation without local kisspeptin signaling in the testis and epididymis. Thus, testosterone supplementation would restore spermatogenesis of male mammals showing hypogonadotropic hypogonadism with genetic inactivation of the KISS1/Kiss1 gene.

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  34. Conditional kisspeptin neuron-specific Kiss1 knockout with newly generated Kiss1-floxed and Kiss1-cre mice replicates a hypogonadal phenotype of global Kiss1 knockout mice Reviewed

    Kana Ikegami, Teppei Goto, Sho Nakamura, Youki Watanabe, Arisa Sugimoto, Sutisa Majarune, Kei Horihata, Mayuko Nagae, Junko Tomikawa, Takuya Imamura, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Kei Ichiro Maeda, Hiroko Tsukamura, Yoshihisa Uenoyama

    Journal of Reproduction and Development   Vol. 66 ( 4 ) page: 359 - 367   2020.8

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    © 2020 by the Society for Reproduction and Development. The present study aimed to evaluate whether novel conditional kisspeptin neuron-specific Kiss1 knockout (KO) mice utilizing the Cre-loxP system could recapitulate the infertility of global Kiss1 KO models, thereby providing further evidence for the fundamental role of hypothalamic kisspeptin neurons in regulating mammalian reproduction. We generated Kiss1-floxed mice and hypothalamic kisspeptin neuron-specific Cre-expressing transgenic mice and then crossed these two lines. The conditional Kiss1 KO mice showed pubertal failure along with a suppression of gonadotropin secretion and ovarian atrophy. These results indicate that newly-created hypothalamic Kiss1 KO mice obtained by the Cre-loxP system recapitulated the infertility of global Kiss1 KO models, suggesting that hypothalamic kisspeptin, but not peripheral kisspeptin, is critical for reproduction. Importantly, these Kiss1-floxed mice are now available and will be a valuable tool for detailed analyses of roles of each population of kisspeptin neurons in the brain and peripheral kisspeptin-producing cells by the spatiotemporal-specific manipulation of Cre expression.

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  35. Peripheral administration of sb223412, a selective neurokinin-3 receptor antagonist, suppresses pulsatile luteinizing hormone secretion by acting on the gonadotropin-releasing hormone pulse generator in estrogen-treated ovariectomized female goats Reviewed

    Takuya Sasaki, Tomoya Sonoda, Ryoki Tatebayashi, Yuri Kitagawa, Shinya Oishi, Koki Yamamoto, Nobutaka Fujii, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Fuko Matsuda, Yasuhiro Morita, Shuichi Matsuyama, Satoshi Ohkura

    Journal of Reproduction and Development   Vol. 66 ( 4 ) page: 351 - 357   2020.8

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    © 2020 by the Society for Reproduction and Development. Accumulating evidence suggests that KNDy neurons located in the hypothalamic arcuate nucleus (ARC), which are reported to express kisspeptin, neurokinin B, and dynorphin A, are indispensable for the gonadotropin-releasing hormone (GnRH) pulse generation that results in rhythmic GnRH secretion. The aims of the present study were to investigate the effects of peripheral administration of the neurokinin 3 receptor (NK3R/TACR3, a receptor for neurokinin B) antagonist, SB223412, on GnRH pulse-generating activity and pulsatile luteinizing hormone (LH) secretion in ovariectomized Shiba goats treated with luteal phase levels of estrogen. The NK3R antagonist was infused intravenously for 4 h {0.16 or 1.6 mg/ (kg body weight [BW]·4 h)} during which multiple unit activity (MUA) in the ARC was recorded, an electrophysiological technique commonly employed to monitor GnRH pulse generator activity. In a separate experiment, the NK3R antagonist (40 or 200 mg/[kg BW·day]) was administered orally for 7 days to determine whether the NK3R antagonist could modulate pulsatile LH secretion when administered via the oral route. Intravenous infusion of the NK3R antagonist significantly increased the interval of episodic bursts of MUA compared with that of the controls. Oral administration of the antagonist for 7 days also significantly prolonged the interpulse interval of LH pulses. The results of this study demonstrate that peripheral administration of an NK3R antagonist suppresses pulsatile LH secretion by acting on the GnRH pulse generator, suggesting that NK3R antagonist administration could be used to modulate reproductive functions in ruminants.

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  36. Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice Reviewed

    Shiori Minabe, Sho Nakamura, Eri Fukushima, Marimo Sato, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Junko Tomikawa, Takuya Imamura, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Fuko Matsuda

    Journal of Reproduction and Development   Vol. 66 ( 4 ) page: 369 - 375   2020.8

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    © 2020 by the Society for Reproduction and Development. Accumulating evidence suggests that kisspeptin-GPR54 signaling is indispensable for gonadotropin-releasing hormone (GnRH)/gonadotropin secretion and consequent reproductive functions in mammals. Conventional Kiss1 knockout (KO) mice and rats are reported to be infertile. To date, however, no study has investigated the effect of inducible central Kiss1 KO/knockdown on pulsatile gonadotropin release in male mammals. Here we report an in vivo analysis of inducible conditional Kiss1 knockdown male mice. The mice were generated by a bilateral injections of either adeno-associated virus (AAV) vectors driving Cre recombinase (AAV-Cre) or AAV vectors driving GFP (AAV-GFP, control) into the hypothalamic arcuate nucleus (ARC) of Kiss1-floxed male mice, in which exon 3 of the Kiss1 gene were floxed with loxP sites. Four weeks after the AAV-Cre injection, the mice showed a profound decrease in the both number of ARC Kiss1-expressing cells and the luteinizing hormone (LH) pulse frequency. Interestingly, pulsatile LH secretion was apparent 8 weeks after the AAV-Cre injection despite the suppression of ARC Kiss1 expression. The control Kiss1-floxed mice infected with AAV-GFP showed apparent LH pulses and Kiss1 expression in the ARC at both 4 and 8 weeks after the AAV-GFP injection. These results with an inducible conditional Kiss1 knockdown in the ARC of male mice suggest that ARC kisspeptin neurons are responsible for pulsatile LH secretion in male mice, and indicate the possibility of a compensatory mechanism that restores GnRH/LH pulse generation.

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  37. Establishment of immortalised cell lines derived from female Shiba goat KNDy and GnRH neurones Reviewed International journal

    Yuta Suetomi, Ryoki Tatebayashi, Shuhei Sonoda, Arisa Munetomo, Shuichi Matsuyama, Naoko Inoue, Yoshihisa Uenoyama, Yukari Takeuchi, Hiroko Tsukamura, Satoshi Ohkura, Fuko Matsuda

    Journal of Neuroendocrinology   Vol. 32 ( 6 ) page: e12857   2020.6

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    © 2020 British Society for Neuroendocrinology Kisspeptin plays a critical role in governing gonadotrophin-releasing hormone (GnRH)/gonadotrophin secretion and subsequent reproductive function in mammals. The hypothalamic arcuate nucleus (ARC) kisspeptin neurones, which co-express neurokinin B (NKB) and dynorphin A (Dyn) and are referred to as KNDy neurones, are considered to be involved in GnRH generation. The present study aimed to establish cell lines derived from goat KNDy and GnRH neurones. Primary-cultured cells of female Shiba goat foetal hypothalamic ARC and preoptic area (POA) tissues were immortalised with the infection of lentivirus containing the simian virus 40 large T-antigen gene. Clones of the immortalised cells were selected by the gene expression of a neuronal marker, and then the neurone-derived cell clones were further selected by the gene expression of KNDy or GnRH neurone markers. As a result, we obtained a KNDy neurone cell line (GA28) from the ARC, as well as two GnRH neurone cell lines (GP11 and GP31) from the POA. Immunocytochemistry revealed the expression of kisspeptin, NKB and Dyn in GA28 cells, as well as GnRH in GP11 and GP31 cells. GnRH secretion from GP11 and GP31 cells into the media was confirmed by an enzyme immunoassay. Moreover, kisspeptin challenge increased intracellular Ca2+ levels in subsets of both GP11 and GP31 cells. Kisspeptin mRNA expression in GA28 cells, which expressed the oestrogen receptor alpha gene, was significantly reduced by 17β-oestradiol treatment. Furthermore, the transcriptional core promoter and repressive regions of the goat NKB gene were detected using GA28 cells. In conclusion, we have established goat KNDy and GnRH neurone cell lines that could be used to analyse molecular and cellular mechanisms regulating KNDy and GnRH neurones in vitro, facilitating the clarification of reproductive neuroendocrine mechanisms in ruminants.

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  38. Retinoblastoma binding protein 7 is involved in Kiss1 mRNA upregulation in rodents Reviewed

    Kei Horihata, Naoko Inoue, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 66 ( 2 ) page: 125 - 133   2020.4

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    © 2020 by the Society for Reproduction and Development. Kisspeptin, encoded by Kiss1, is essential for reproduction in mammals. Kiss1 expression is regulated by estrogen via histone acetylation in the Kiss1 promotor region. Thus, elucidation of histone modification factor(s) involved in the regulation of Kiss1 expression is required to gain further understanding of the mechanisms of its control. The RNA-seq analysis of isolated kisspeptin neurons, obtained from the arcuate nucleus (ARC) of female rats, revealed that Rbbp7, encoding retinoblastoma binding protein 7 (RBBP7), a member of histone modification and chromatin remodeling complexes, is highly expressed in the ARC kisspeptin neurons. Thus, the present study aimed to investigate whether RBBP7 is involved in Kiss1 expression. Histological analysis using in situ hybridization (ISH) revealed that Rbbp7 expression was located in several hypothalamic nuclei, including the ARC and the anteroventral periventricular nucleus (AVPV), where kisspeptin neurons are located. Double ISH for Rbbp7 and Kiss1 showed that a majority of kisspeptin neurons (more than 85%) expressed Rbbp7 mRNA in both the ARC and the AVPV of female rats. Further, Rbbp7 mRNA knockdown significantly decreased in vitro expression of Kiss1 in a mouse immortalized kisspeptin neuronal cell line (mHypoA-55). Estrogen treatment significantly decreased and increased Kiss1 mRNA levels in the ARC and AVPV of ovariectomized female rats, respectively, but failed to affect Rbbp7 mRNA levels in both the nuclei. Taken together, these findings suggest that RBBP7 is involved in the upregulation of Kiss1 expression in kisspeptin neurons of rodents in an estrogen-independent manner.

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  39. Establishment of long-term chronic recording technique of in vivo ovarian parenchymal temperature in Japanese black cows Reviewed

    Yasuhiro Morita, Riho Ozaki, Akihisa Mukaiyama, Takuya Sasaki, Ryoki Tatebayashi, Ai Morishima, Yuri Kitagawa, Reika Suzumura, Ryoya Abe, Hiroko Tsukamura, Shuichi Matsuyama, Satoshi Ohkura

    Journal of Reproduction and Development   Vol. 66 ( 3 ) page: 271 - 275   2020

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    © 2020 by the Society for Reproduction and Development. The reproductive performance of cattle can be suppressed by heat stress. Reproductive organ temperature, especially ovarian temperature, may affect follicle development and ovulation. The establishment of a technique for longterm measurement of ovarian temperature could prove useful in understanding the mechanisms underlying the temperaturedependent changes in follicular development and subsequent ovulation in cows. Here we report a novel method facilitating long-term and continuous recording of ovarian parenchymal temperature in cows. The method revealed that the ovarian temperature in the luteal phase was constantly maintained lower than the vaginal temperature, and that the diurnal temperature variation in the ovary was significantly greater than that in the vagina, suggesting that the ovaries may require a lower temperature than other organs to maintain their functions. This novel method could be used for the further understanding of ovarian functions during estrous cycles in cows.

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  40. GnRH(1-5), a metabolite of gonadotropin-releasing hormone, enhances luteinizing hormone release via activation of kisspeptin neurons in female rats Reviewed

    Nahoko Ieda, Assadullah, Shiori Minabe, Kana Ikegami, Youki Watanabe, Yusuke Sugimoto, Arisa Sugimoto, Narumi Kawai, Hirotaka Ishii, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Endocrine Journal   Vol. 67 ( 4 ) page: 409 - 418   2020

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    © The Japan Endocrine Society. Accumulating evidence suggests that kisspeptin neurons in the arcuate nucleus (ARC), which coexpress neurokinin B and dynorphin, are involved in gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) pulse generation, while the anteroventral periventricular nucleus (AVPV) kisspeptin neurons are responsible for GnRH/LH surge generation. The present study aims to examine whether GnRH(1-5), a GnRH metabolite, regulates LH release via kisspeptin neurons. GnRH(1-5) was intracerebroventricularly injected to ovariectomized and estrogen-treated Wistar-Imamichi female rats. Immediately after the central GnRH(1-5) administration at 2 nmol, plasma LH concentration increased, resulting in significantly higher levels of the area under the curve and baseline of plasma LH concentrations compared to vehicle-injected controls. On the other hand, in Kiss1 knockout rats, GnRH(1-5) administration failed to affect LH secretion, suggesting that the facilitatory effect of GnRH(1-5) on LH release is mediated by kisspeptin neurons. Double in situ hybridization (ISH) for Kiss1 and Gpr101, a GnRH(1-5) receptor gene, revealed that few Kiss1-expressing cells coexpress Gpr101 in both ARC and AVPV. On the other hand, double ISH for Gpr101 and Slc17a6, a glutamatergic marker gene, revealed that 29.2% of ARC Gpr101-expressing cells coexpress Slc17a6. Further, most of the AVPV and ARC Kiss1-expressing cells coexpress Grin1, a gene encoding a subunit of NMDA receptor. Taken together, these results suggest that the GnRH(1-5)-GPR101 signaling facilitates LH release via indirect activation of kisspeptin neurons and that glutamatergic neurons may mediate the signaling. This provides a new aspect of kisspeptin-and GnRH-neuronal communication with the presence of stimulation from GnRH to kisspeptin neurons in female rats.

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  41. Role of kisspeptin neurons as a GnRH surge generator: Comparative aspects in rodents and non-rodent mammals Reviewed International journal

    Fuko Matsuda, Satoshi Ohkura, Fumie Magata, Arisa Munetomo, Jing Chen, Marimo Sato, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Journal of Obstetrics and Gynaecology Research   Vol. 45 ( 12 ) page: 2318 - 2329   2019.12

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    © 2019 Japan Society of Obstetrics and Gynecology Ovulation is an essential phenomenon for reproduction in mammalian females along with follicular growth. It is well established that gonadal function is controlled by the neuroendocrine system called the hypothalamus-pituitary-gonadal (HPG) axis. Gonadotropin-releasing hormone (GnRH) neurons, localized in the hypothalamus, had been considered to be the head in governing the HPG axis for a long time until the discovery of kisspeptin. In females, induction of ovulation and folliculogenesis has been linked to a surge mode and pulse mode of GnRH releases, respectively. The mechanisms of how the two modes of GnRH are differently regulated had long remained elusive. The discovery of kisspeptin neurons, distributed in two hypothalamic nuclei, such as the arcuate nucleus in the caudal hypothalamus and preoptic area or the anteroventral periventricular nucleus in the rostral hypothalamic regions, and analyses of the detailed functions of kisspeptin neurons have led marked progress on the understanding of different mechanisms regulating GnRH surges (ovulation) and GnRH pulses (folliculogenesis). The present review will focus on the role of kisspeptin neurons as the GnRH surge generator, including the sexual differentiation of the surge generation system and factors that regulate the surge generator. Comparative aspects between mammalian species are especially focused on.

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  42. Ad libitum feeding triggers puberty onset associated with increases in arcuate kiss1 and pdyn expression in growth-retarded rats Reviewed

    Sutisa Majarune, Pelden Nima, Arisa Sugimoto, Mayuko Nagae, Naoko Inoue, Hiroko Tsukamura, Yoshihisa Uenoyama

    Journal of Reproduction and Development   Vol. 65 ( 5 ) page: 397 - 406   2019.10

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    © 2019 by the Society for Reproduction and Development. Increasing evidence shows that puberty onset is largely dependent on body weight rather than chronological age. To investigate the mechanism involved in the energetic control of puberty onset, the present study examined effects of chronic food restriction during the prepubertal period and the resumption of ad libitum feeding for 24 and 48 h on estrous cyclicity, Kiss1 (kisspeptin gene), Tac3 (neurokinin B gene) and Pdyn (dynorphin A gene) expression in the hypothalamus, luteinizing hormone (LH) secretion and follicular development in female rats. When animals weighed 75 g, they were subjected to a restricted feeding to retard growth to 70–80 g by 49 days of age. Then, animals were subjected to ad libitum feeding or remained food-restricted. The growth-retarded rats did not show puberty onset associated with suppression of both Kiss1 and Pdyn expression in the arcuate nucleus (ARC). 24-h ad libitum feeding increased tonic LH secretion and the number of Graafian and non-Graafian tertiary follicles with an increase in the numbers of ARC Kiss1-and Pdyn-expressing cells. 48-h ad libitum feeding induced the vaginal proestrus and a surge-like LH increase with an increase in Kiss1-expressing cells in the anteroventral periventricular nucleus (AVPV). These results suggest that the negative energy balance causes pubertal failure with suppression of ARC Kiss1 and Pdyn expression and then subsequent gonadotropin secretion and ovarian function, while the positive energetic cues trigger puberty onset via an increase in ARC Kiss1 and Pdyn expression and thus gonadotropin secretion and follicular development in female rats.

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  43. Peripheral administration of κ-opioid receptor antagonist stimulates gonadotropin-releasing hormone pulse generator activity in ovariectomized, estrogen-treated female goats Reviewed

    T. Sasaki, D. Ito, T. Sonoda, Y. Morita, Y. Wakabayashi, T. Yamamura, H. Okamura, S. Oishi, T. Noguchi, N. Fujii, Y. Uenoyama, H. Tsukamura, K. I. Maeda, F. Matsuda, S. Ohkura

    Domestic Animal Endocrinology   Vol. 68   page: 83 - 91   2019.7

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    © 2019 Elsevier Inc. Pulsatile gonadotropin-releasing hormone (GnRH) secretion is indispensable for reproduction in mammals. Kisspeptin neurons in the hypothalamic arcuate nucleus (ARC), referred to as KNDy neurons because of the coexpression of neurokinin B and dynorphin A, are considered as components of the GnRH pulse generator that produces rhythmic GnRH secretion. The present study aimed to investigate if peripheral administration of PF-4455242, a κ-opioid receptor (KOR, a dynorphin A receptor) antagonist, facilitates pulsatile luteinizing hormone (LH) secretion and GnRH pulse generator activity in estrogen-treated ovariectomized Shiba goats to determine the possibility of using KOR antagonists to artificially control ovarian activities. PF-4455242 was intravenously infused for 4 h (1 or 10 μmol/kg body weight/4 h) or as a single subcutaneous injection (1 or 10 μmol/kg body weight). In a separate experiment, the same KOR antagonist (10 μmol/kg body weight/4 h) was intravenously infused during the recording of multiple unit activity (MUA) in the ARC that reflects the activity of the GnRH pulse generator to test the effects of KOR antagonist administration on GnRH pulse generator activity. Intravenous infusion and single subcutaneous injection of the KOR antagonist significantly increased the frequency of LH pulses compared with controls. Intravenous infusion of KOR antagonist also significantly increased the frequency of episodic bursts in the MUA. The present study demonstrates that peripherally administered KOR antagonist stimulates pulsatile LH secretion by acting on the GnRH pulse generator, and peripheral administration of PF-4455242 can be used to facilitate pulsatile LH secretion, which in turn facilitates ovarian activities in farm animals.

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  44. Central mechanism controlling pubertal onset in mammals: A triggering role of kisspeptin International journal

    Yoshihisa Uenoyama, Naoko Inoue, Sho Nakamura, Hiroko Tsukamura

    Frontiers in Endocrinology   Vol. 10 ( MAY ) page: 312 - 312   2019.5

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    Copyright © 2019 Uenoyama, Inoue, Nakamura and Tsukamura. Pubertal onset is thought to be timed by an increase in pulsatile gonadotropin-releasing hormone (GnRH)/gonadotropin secretion in mammals. The underlying mechanism of pubertal onset in mammals is still an open question. Evidence accumulated in the last 15 years suggests that kisspeptin/neurokinin B/dynorphin A (KNDy) neurons in the hypothalamic arcuate nucleus play a key role in pubertal onset by triggering pulsatile GnRH/gonadotropin secretin in mammals. Specifically, KNDy neurons are now considered a part of GnRH pulse generator, in which neurokinin B facilitates and dynorphin A inhibits, the synchronized discharge of KNDy neurons in autocrine and/or paracrine manners. Kisspeptin serves as a potent secretagogue of GnRH secretion and thus its release is fundamental to pubertal increase in GnRH/gonadotropin secretion in mammals. Proposed mechanisms inhibiting Kiss1 (kisspeptin gene) expression during childhood to juvenile varies from species to species: we envisage that negative feedback action of estrogen plays a key role in the inhibition of Kiss1 expression in KNDy neurons in rodents and sheep, whereas estrogen-independent inhibition of kisspeptin secretion by γ-amino butyric acid or neuropeptide Y are suggested to be responsible for the pre-pubertal suppression of GnRH/gonadotropin secretion in primates. Taken together, the timing of pubertal onset is postulated to be controlled by upstream regulators for kisspeptin biosynthesis and secretion in mammals.

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  45. Neonatal estrogen causes irreversible male infertility via specific suppressive action on hypothalamic kiss1 neurons Reviewed International journal

    Shiori Minabe, Marimo Sato, Naoko Inoue, Youki Watanabe, Fumie Magata, Fuko Matsuda, Yoshihisa Uenoyama, Hitoshi Ozawa, Hiroko Tsukamura

    Endocrinology   Vol. 160 ( 5 ) page: 1223 - 1233   2019.5

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    Copyright © 2019 Endocrine Society. Aberrant exposure to estrogen-like compounds during the critical developmental period may cause improper hypothalamic programming, thus resulting in reproductive dysfunction in adulthood in male mammals. Kisspeptin-neurokinin B-dynorphin A (KNDy) neurons in the arcuate nucleus (ARC) have been suggested to govern tonic GnRH/gonadotropin release to control reproduction in male mammals. In this study, we report that chronic exposure to supraphysiological levels of estrogen during the neonatal period caused an irreversible suppression of KNDy genes in the ARC, resulting in reproductive dysfunction in male rats. Daily estradiol benzoate (EB) administration from days 0 to 10 postpartum caused smaller seminiferous tubules, abnormal spermatogenesis, and a decrease in plasma testosterone in adult male rats. The neonatal EB treatment profoundly suppressed LH pulse and ARC KNDy gene expression at adulthood, but it failed to affect the number of GnRH gene-expressing cells in male rats. The EB treatment failed to affect gene expression of other neuropeptides, such as GHRH, proopiomelanocortin, and agouti-related protein in the ARC, suggesting that ARC KNDy neurons would be a specific target of neonatal estrogen to cause male reproductive dysfunction. Because LH secretory responses to kisspeptin challenge and GnRH expression were spared in male rats with the EB treatment, LH pulse suppression is most probably due to ARC KNDy deficiency. Taken together, the current study indicates that chronic exposure to estrogenic chemicals in the developing brain causes a defect of ARC KNDy neurons, resulting in an inhibition of pulsatile GnRH/LH release and the failure of spermatogenesis and steroidogenesis.

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  46. Morphological analysis for neuronal pathway from the hindbrain ependymocytes to the hypothalamic kisspeptin neurons Reviewed

    Chikaya Deura, Shiori Minabe, Kana Ikegami, Naoko Inoue, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 65 ( 2 ) page: 129 - 137   2019.4

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    © 2019 by the Society for Reproduction and Development. Hindbrain ependymocytes are postulated to have a glucose-sensing role in regulating gonadal functions. Previous studies have suggested that malnutrition-induced suppression of gonadotropin secretion is mediated by noradrenergic inputs from the A2 region in the solitary tract nucleus to the paraventricular nucleus (PVN), and by corticotropin-releasing hormone (CRH) release in the hypothalamus. However, no morphological evidence to indicate the neural pathway from the hindbrain ependymocytes to hypothalamic kisspeptin neurons, a center for reproductive function in mammals, currently exists. The present study aimed to examine the existence of a neuronal pathway from the hindbrain ependymocytes to kisspeptin neurons in the arcuate nucleus (ARC) and anteroventral periventricular nucleus (AVPV). To determine this, wheat-germ agglutinin (WGA), a trans-synaptic tracer, was injected into the fourth ventricle (4V) in heterozygous Kiss1-tandem dimer Tomato (tdTomato) rats, where kisspeptin neurons were visualized by tdTomato fluorescence. 48 h after the WGA injection, brain sections were taken from the forebrain, midbrain and hindbrain and subjected to double immunohistochemistry for WGA and dopamine β-hydroxylase (DBH) or CRH. WGA immunoreactivities were found in vimentin-immunopositive ependymocytes of the 4V and the central canal (CC), but not in the third ventricle. The WGA immunoreactivities were detected in some tdTomato-expressing cells in the ARC and AVPV, DBH-immunopositive cells in the A1–A7 noradrenergic nuclei, and CRHimmunopositive cells in the PVN. These results suggest that the hindbrain ependymocytes have neuronal connections with the kisspeptin neurons, most probably via hindbrain noradrenergic and CRH neurons to relay low energetic signals for regulation of reproduction.

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  47. Somatostatin-somatostatin receptor 2 signaling mediates LH pulse suppression in lactating rats Reviewed International journal

    Arisa Sugimoto, Hitomi Tsuchida, Nahoko Ieda, Kana Ikegami, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Endocrinology   Vol. 160 ( 2 ) page: 473 - 483   2019.2

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    Copyright © 2019 Endocrine Society Follicular development and ovulation are profoundly suppressed during lactation in mammals. This suppression is suggested to be mainly due to the suckling-induced inhibition of kisspeptin gene (Kiss1) expression in the arcuate nucleus (ARC) and consequent inhibition of pulsatile GnRH/LH release. We examined whether central somatostatin (SST) signaling mediates the suckling-induced suppression of pulsatile LH secretion. SST has been reported to be expressed in the posterior intralaminar thalamic nucleus (PIL), where the suckling stimulus is postulated to be relayed to the hypothalamus during lactation. SST inhibitory receptors (SSTRs) are abundantly expressed in the ARC, where kisspeptin/neurokinin B/dynorphin A (KNDy) neurons are located. Histological and quantitative studies revealed that the suckling stimulus increased the number of SST-expressing cells in the PIL, and Sstr2 expression in the ARC. Furthermore, a central injection of an SSTR2 antagonist caused a significant increase in pulsatile LH release in lactating rats. Double labeling of Sstr2 and the neurokinin B gene, as a marker for ARC KNDy neurons, showed Sstr2 expression was abundantly detected in the ARC, but few KNDy neurons coexpressed Sstr2 in lactating rats. Taken together, these findings suggest the suckling-induced activation of SST-SSTR2 signaling mediates, at least in part, the suppression of pulsatile LH secretion during lactation in rats, probably via the indirect effects of SST on KNDy neurons. These results provide a new aspect on the role of central SST-SSTR signaling in understanding the mechanism underlying lactational anestrus.

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  48. The roles of kisspeptin in the mechanism underlying reproductive functions in mammals Invited

    Yoshihisa Uenoyama, Naoko Inoue, Ichiro Kei-Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 64 ( 6 ) page: 469 - 476   2018.12

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    © 2018 by the Society for Reproduction and Development. Kisspeptin, identified as a natural ligand of GPR54 in 2001, is now considered as a master regulator of puberty and subsequent reproductive functions in mammals. Our previous studies using Kiss1 knockout (KO) rats clearly demonstrated the indispensable role of kisspeptin in gonadotropin-releasing hormone (GnRH)/gonadotropin secretion. In addition, behavioral analyses of Kiss1 KO rats revealed an organizational effect of kisspeptin on neural circuits controlling sexual behaviors. Our studies using transgenic mice carrying a region-specific Kiss1 enhancer-driven reporter gene provided a clue as to the mechanism by which estrogen regulates Kiss1 expression in hypothalamic kisspeptin neurons. Analyses of Kiss1 expression and gonadotropin secretion during the pubertal transition shed light on the mechanism triggering GnRH/gonadotropin secretion at the onset of puberty in rats. Here, we summarize data obtained from the aforementioned studies and revisit the physiological roles of kisspeptin in the mechanism underlying reproductive functions in mammals.

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  49. Co-expression of the calcitonin receptor gene in the hypothalamic kisspeptin neurons in female rats Reviewed

    Assadullah, Nahoko Ieda, Narumi Kawai, Hirotaka Ishii, Kunio Ihara, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura

    Reproductive Medicine and Biology   Vol. 17 ( 2 ) page: 164 - 172   2018.4

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    © 2018 The Authors. Reproductive Medicine and Biology published by John Wiley & Sons Australia, Ltd on behalf of Japan Society for Reproductive Medicine. Purpose: Hypothalamic kisspeptin neurons are considered to play a critical role in regulating mammalian reproduction and integrating humoral and neuronal inputs that control gonadotropin-releasing hormone (GnRH)/gonadotropin release. The present study aimed to investigate the upstream regulator candidates for kisspeptin neurons. Methods: Visualized kisspeptin neurons that were taken from the arcuate nucleus (ARC) of Kiss1-tdTomato rats were subjected to next-generation sequencing (NGS) analysis. In situ hybridization (ISH) for the calcitonin receptor gene (Calcr) was performed throughout the whole forebrain of ovariectomized wild-type female rats that had been implanted with a negative feedback level of estrogen, because the Calcr expression was evident in the ARC kisspeptin neurons from the NGS analysis. Then, a double ISH was performed for the Calcr and kisspeptin gene (Kiss1) in the brain regions, containing either the anteroventral periventricular nucleus (AVPV) or ARC of the female rats. Results: The NGS analysis revealed that the Calcr was highly expressed in the ARC kisspeptin neurons. It was found that the Calcr was co-expressed in 12% and 22% of the Kiss1-expressing cells in the ARC and AVPV, respectively. Conclusion: The present study suggests that calcitonin receptor signaling could be involved in the regulation of reproductive function through the direct control of the ARC and/or AVPV kisspeptin neurons, and then GnRH/gonadotropin release.

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  50. Fetal/perinatal Programming Causing Sexual Dimorphism of the Kisspeptin-GnRH Neuronal Network Reviewed

    Hiroko Tsukamura, Kei Ichiro Maeda, Yoshihisa Uenoyama

    The GnRH Neuron and its Control     page: 43 - 60   2018.4

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    © 2018 John Wiley & Sons Ltd. All rights reserved. Female mammals show two modes of gonadotropin-releasing hormone (GnRH)/gonadotropin release throughout the ovarian cycle: surges for induction of ovulation and pulses for follicular development and steroidogenesis. In contrast, males show only the pulsatile mode of GnRH/gonadotropin release, which is responsible for testosterone secretion and spermatogenesis. The GnRH surge in the female is due to a positive feedback action of pre-ovulatory levels of estradiol (E2) and this involves a major action at the level of the hypothalamus. Kisspeptin neurons in the preoptic area (POA), and in rodents specifically in the anteroventral periventricular nucleus (AVPV) and periventricular nucleus (PeN) of the POA are considered a major target for the positive feedback action of E2 (Fig. 1). On the other hand, the arcuate nucleus (ARC) kisspeptin neurons are considered to be involved in GnRH pulse generation. The inability of estrogen to induce a luteinizing hormone (LH) surge in male rodents is considered to be due to an action of perinatal testicular testosterone secretion on the neuronal network regulating GnRH release. On the other hand, this sexual dimorphism of the GnRH/LH surge system is not obvious in some mammalian species, such as primates and goats, and the surge generating system is conserved in males, as reflected by the ability of preovulatory levels of estrogen to induce surge-like increases of LH in these species. The present chapter focuses on recent progress in our understanding of the mechanisms underlying sexual dimorphism of the GnRH-releasing system in rodents, and we summarize the role of kisspeptin neurons as a target of perinatal testicular androgen during brain development.

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  51. Evaluation of heat stress response in crossbred dairy cows under tropical climate by analysis of heart rate variability

    Chan Bun, Youki Watanabe, Yoshihisa Uenoyama, Naoko Inoue, Nahoko Ieda, Fuko Matsuda, Hiroko Tsukamura, Masayoshi Kuwahara, Kei Ichiro Maeda, Satoshi Ohkura, Vutha Pheng

    Journal of Veterinary Medical Science   Vol. 80 ( 1 ) page: 181 - 185   2018.1

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    © 2018 The Japanese Society of Veterinary Science The present study aims to examine the effect of tropical temperatures on autonomic nervous activity in Cambodian dairy cattle by analyzing heart rate variability (HRV). Holter-type electrocardiograms were recorded in adult crossbred cows (Cambodian native × Holstein) either in a sheltered area or under direct sunlight. Rectal temperatures and heart rates increased in animals under direct sunlight as compared to those in the shelter. The power spectral analysis of HRV revealed that three out of the five cows studied underwent a decrease in parasympathetic nervous activity under direct sunlight with the remaining two cows showing no apparent change. The HRV analysis would prove to be a useful tool to reveal information about heat tolerance in dairy cows.

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  52. Obituary - Professor Kei-ichiro Maeda Reviewed

    Hiroko Tsukamura

    ENDOCRINE JOURNAL   Vol. 65 ( 9 ) page: 879 - 880   2018

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  53. SB223412, a neurokinin-3 receptor-selective antagonist, suppresses testosterone secretion in male guinea pigs Reviewed International journal

    Sho Nakamura, Yoshiko Ito, Koki Yamamoto, Chudai Takahashi, Mingdao Dai, Miyu Tanahashi, Yoshihisa Uenoyama, Hiroko Tsukamura, Shinya Oishi, Kei ichiro Maeda, Fuko Matsuda

    Theriogenology   Vol. 102   page: 183 - 189   2017.10

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    © 2017 Elsevier Inc. Guinea pigs are important zoo animals and have been recommended for animal-assisted activities or therapy, however there are problems concerning testosterone inducing aggressive or sexual behaviors in male guinea pigs. Testicular testosterone secretion is regulated by pulsatile gonadotropin releasing hormone (GnRH)/luteinizing hormone (LH) release in mammals. The mechanism generating GnRH/LH pulses is thought to be governed by kisspeptin neurons, which coexpress neurokinin B (NKB) and dynorphin A (Dyn), in the arcuate nucleus (ARC). Kisspeptin neurons in the ARC are frequently referred to as KNDy neurons. The purpose of this study was to examine whether the antagonization of NKB-neurokinin-3 receptor (NK3R) signaling can manipulate testosterone secretion in male guinea pigs. A single subcutaneous administration or 7 days of oral administration of an NK3R-selective antagonist, SB223412 (50 mg/body), significantly decreased plasma testosterone levels in male guinea pigs. In vitro binding assays confirmed that SB223412 has a high affinity to guinea pig NK3R. These results suggest that SB223412 could be used as an orally-available compound to suppress testosterone levels in male guinea pigs. Double labeling in situ hybridization of kisspeptin and either NKB or Dyn showed that kisspeptin-expressing neurons contained NKB (77.9%) or Dyn (62.3%) in the ARC, suggesting the presence of KNDy neurons in the ARC of guinea pigs. In conclusion, the present study shows that SB223412 could be a candidate compound to suppress testosterone secretion in male guinea pigs for controlling sexual and aggressive behaviors in the species.

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  54. Long-term neonatal estrogen exposure causes irreversible inhibition of LH pulses by suppressing arcuate kisspeptin expression via estrogen receptors α and β in female rodents Reviewed International journal

    Shiori Minabe, Nahoko Ieda, Youki Watanabe, Naoko Inoue, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Endocrinology   Vol. 158 ( 9 ) page: 2918 - 2929   2017.9

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    © Copyright 2017 Endocrine Society. Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, because the developing brain is highly sensitive to estrogens. In the present study, we report that long-term exposure to supraphysiological doses of estrogen during the neonatal critical period causes irreversible suppression of Kiss1/kisspeptin expression in the arcuate nucleus (ARC) via estrogen receptor-alpha (ERα) and ERβ, resulting in reproductive dysfunction in female rats. Daily estradiol-benzoate (EB) administration from days 0 to 10 postpartum caused persistent vaginal diestrus in female rats. The female rats showed profound suppression of pulsatile luteinizing hormone (LH) release and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. In contrast, female rats treated with a single EB injection at day 5 postpartum exhibited persistent vaginal estrus and showed comparable LH pulses and numbers of ARC Kiss1-expressing cells to vehicle-treated controls after ovariectomy at adulthood. Because the LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen exposure, the LH pulse suppression was most probably due to ARC kisspeptin deficiency. Furthermore, neonatal estrogenmight act through both ERα and ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type mice but not in ERα or ERβ knockout mice. Taken together, long-term exposure to supraphysiological doses of estrogen in the developing brainmight cause defects in ARC kisspeptin neurons via ERα and ERβ, resulting in inhibition of pulsatile LH release and lack of estrous cyclicity.

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  55. Enhancement of the luteinising hormone surge by male olfactory signals is associated with anteroventral periventricular Kiss1 cell activation in female rats Reviewed

    Y. Watanabe, K. Ikegami, R. Ishigaki, N. Ieda, Y. Uenoyama, K. I. Maeda, H. Tsukamura, N. Inoue

    Journal of Neuroendocrinology   Vol. 29 ( 8 )   2017.8

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    © 2017 British Society for Neuroendocrinology Olfactory stimuli play an important role in regulating reproductive functions in mammals. The present study investigated the effect of olfactory signals derived from male rats on kisspeptin neuronal activity and luteinising hormone (LH) secretion in female rats. Wistar-Imamichi strain female rats were ovariectomised (OVX) and implanted with preovulatory levels of 17β-oestradiol (E2). OVX+E2 rats were killed 1 hour after exposure to either: clean bedding, female-soiled bedding or male-soiled bedding. Dual staining for Kiss1 mRNA in situ hybridisation and c-Fos immunohistochemistry revealed that the numbers of Kiss1-expressing cells and c-Fos-immunopositive Kiss1-expressing cells in the anteroventral periventricular nucleus (AVPV) were significantly higher in OVX+E2 rats exposed to male-soiled bedding than those of the other groups. No significant difference was found with respect to the number of c-Fos-immunopositive Kiss1-expressing cells in the arcuate nucleus and c-Fos-immunopositive Gnrh1-expressing cells between the groups. The number of c-Fos-immunopositive cells was also significantly higher in the limbic system consisting of several nuclei, such as the bed nucleus of the stria terminalis, the cortical amygdala and the medial amygdala, in OVX+E2 rats exposed to male-soiled bedding than the other groups. OVX+E2 rats exposed to male-soiled bedding showed apparent LH surges, and the peak of the LH surge and area under the curve of LH concentrations in the OVX+E2 group were significantly higher than those of the other two groups. These results suggest that olfactory signals derived from male rats activate AVPV kisspeptin neurones, likely via the limbic system, resulting in enhancement of the peak of the LH surge in female rats. Taken together, the results of the present study suggests that AVPV kisspeptin neurones are a target of olfactory signals to modulate LH release in female rats.

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  56. Evidence of involvement of neurone-glia/neurone-neurone communications via gap junctions in synchronised activity of KNDy neurones Reviewed

    K. Ikegami, S. Minabe, N. Ieda, T. Goto, A. Sugimoto, S. Nakamura, N. Inoue, S. Oishi, A. D. Maturana, M. Sanbo, M. Hirabayashi, K. I. Maeda, H. Tsukamura, Y. Uenoyama

    Journal of Neuroendocrinology   Vol. 29 ( 6 )   2017.6

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    © 2017 British Society for Neuroendocrinology Pulsatile secretion of gonadotrophin-releasing hormone (GnRH)/luteinising hormone is indispensable for the onset of puberty and reproductive activities at adulthood in mammalian species. A cohort of neurones expressing three neuropeptides, namely kisspeptin, encoded by the Kiss1 gene, neurokinin B (NKB) and dynorphin A, localised in the hypothalamic arcuate nucleus (ARC), so-called KNDy neurones, comprises a putative intrinsic source of the GnRH pulse generator. Synchronous activity among KNDy neurones is considered to be required for pulsatile GnRH secretion. It has been reported that gap junctions play a key role in synchronising electrical activity in the central nervous system. Thus, we hypothesised that gap junctions are involved in the synchronised activities of KNDy neurones, which is induced by NKB-NK3R signalling. We determined the role of NKB-NK3R signalling in Ca2+ oscillation (an indicator of neuronal activities) of KNDy neurones and its synchronisation mechanism among KNDy neurones. Senktide, a selective agonist for NK3R, increased the frequency of Ca2+ oscillations in cultured Kiss1-GFP cells collected from the mediobasal hypothalamus of the foetal Kiss1-green fluorescent protein (GFP) mice. The senktide-induced Ca2+ oscillations were synchronised in the Kiss1-GFP and neighbouring glial cells. Confocal microscopy analysis of these cells, which have shown synchronised Ca2+ oscillations, revealed close contacts between Kiss1-GFP cells, as well as between Kiss1-GFP cells and glial cells. Dye coupling experiments suggest cell-to-cell communication through gap junctions between Kiss1-GFP cells and neighbouring glial cells. Connexin-26 and -37 mRNA were found in isolated ARC Kiss1 cells taken from adult female Kiss1-GFP transgenic mice. Furthermore, 18β-glycyrrhetinic acids and mefloquine, which are gap junction inhibitors, attenuated senktide-induced Ca2+ oscillations in Kiss1-GFP cells. Taken together, these results suggest that NKB-NK3R signalling enhances synchronised activities among neighbouring KNDy neurones, and that both neurone-neurone and neurone-glia communications via gap junctions possibly contribute to synchronised activities among KNDy neurones.

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  57. CRISPR/Cas9-mediated genome editing in wild-derived mice: Generation of tamed wild-derived strains by mutation of the a (nonagouti) gene Reviewed International journal

    Michiko Hirose, Ayumi Hasegawa, Keiji Mochida, Shogo Matoba, Yuki Hatanaka, Kimiko Inoue, Tatsuhiko Goto, Hideki Kaneda, Ikuko Yamada, Tamio Furuse, Kuniya Abe, Yoshihisa Uenoyama, Hiroko Tsukamura, Shigeharu Wakana, Arata Honda, Atsuo Ogura

    Scientific Reports   Vol. 7   page: 42476 - 42476   2017.2

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    © 2017 The Author(s). Wild-derived mice have contributed to experimental mouse genetics by virtue of their genetic diversity, which may help increase the chance of identifying novel modifier genes responsible for specific phenotypes and diseases. However, gene targeting using wild-derived mice has been unsuccessful because of the unavailability of stable embryonic stem cells. Here, we report that CRISPR/Cas9-mediated gene targeting can be applied to the Japanese wild-derived MSM/Ms strain (Mus musculus molossinus). We targeted the nonagouti (a) gene encoding the agouti protein that is localized in hair and the brain. We obtained three homozygous knockout mice as founders, all showing black coat colour. While homozygous knockout offspring were physiologically indistinguishable from wild-type litter-mates, they showed specific domesticated behaviours: hypoactivity in the dark phase and a decline in the avoidance of a human hand. These phenotypes were consistent over subsequent generations. Our findings support the empirical hypothesis that nonagouti is a domestication-linked gene, the loss of which might repress aggressive behaviour.

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  58. The roles of kisspeptin revisited: Inside and outside the hypothalamus

    Yoshihisa Uenoyama, Vutha Pheng, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 62 ( 6 ) page: 537 - 545   2016.12

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    © 2016 by the Society for Reproduction and Development. Kisspeptin, encoded by KISS1/Kiss1 gene, is now considered a master regulator of reproductive functions in mammals owing to its involvement in the direct activation of gonadotropin-releasing hormone (GnRH) neurons after binding to its cognate receptor, GPR54. Ever since the discovery of kisspeptin, intensive studies on hypothalamic expression of KISS1/Kiss1 and on physiological roles of hypothalamic kisspeptin neurons have provided clues as to how the brain controls sexual maturation at the onset of puberty and subsequent reproductive performance in mammals. Additionally, emerging evidence indicates the potential involvement of extra-hypothalamic kisspeptin in reproductive functions. Here, we summarize data regarding kisspeptin inside and outside the hypothalamus and revisit the physiological roles of central and peripheral kisspeptins in the reproductive functions of mammals.

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  59. 視床下部による卵胞発育制御機構〜卵胞発育を理解するー知っておくべき基礎知識【卵胞発育の生理】 Invited

    井上直子、束村博子、上野山賀久

    臨床婦人科産科   Vol. 70 ( 12 ) page: 1094 - 1097   2016.12

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  60. Immunohistochemical characterization of the arcuate kisspeptin/ neurokinin b/dynorphin (KNDy) and preoptic kisspeptin neuronal populations in the hypothalamus during the estrous cycle in heifers Reviewed

    Ahmed Saad Ahmed Hassaneen, Yousuke Naniwa, Yuta Suetomi, Shuichi Matsuyama, Koji Kimura, Nahoko Ieda, Naoko Inoue, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Fuko Matsuda, Satoshi Ohkura

    Journal of Reproduction and Development   Vol. 62 ( 5 ) page: 471 - 477   2016.10

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    © 2016 by the Society for Reproduction and Development. Elucidating the physiological mechanisms that control reproduction is an obvious strategy for improving the fertility of cattle and developing new agents to control reproductive functions. The present study aimed to identify kisspeptin neurons in the bovine hypothalamus, clarifying that a central mechanism is also present in the cattle brain, as kisspeptin is known to play an important role in the stimulation of gonadotropin-releasing hormone (GnRH)/gonadotropin secretion in other mammals. To characterize kisspeptin neurons in the bovine hypothalamus, the co-localizations of kisspeptin and neurokinin B (NKB) or kisspeptin and dynorphin A (Dyn) were examined. Hypothalamic tissue was collected from Japanese Black or Japanese Black × Holstein crossbred cows during the follicular and luteal phases. Brain sections, including the arcuate nucleus (ARC) and the preoptic area (POA), were dual immunostained with kisspeptin and either NKB or Dyn. In the ARC, both NKB and Dyn were co-localized in kisspeptin neurons during both the follicular and luteal phases, demonstrating the presence of kisspeptin/NKB/Dyn-containing neurons, referred to as KNDy neurons, in cows. In the POA, no co-localization of kisspeptin with either NKB or Dyn was detected. Kisspeptin expression in the follicular phase was higher than that in the luteal phase, suggesting that kisspeptin expression in the POA is positively controlled by estrogen in cows. The kisspeptin neuronal populations in the ARC and POA likely play important roles in regulating the GnRH pulse and surge, respectively, in cows.

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  61. Neonatal Kisspeptin is Steroid-Independently Required for Defeminisation and Peripubertal Kisspeptin-Induced Testosterone is Required for Masculinisation of the Brain: A Behavioural Study Using Kiss1 Knockout Rats Reviewed

    S. Nakamura, Y. Uenoyama, K. Ikegami, M. Dai, Y. Watanabe, C. Takahashi, M. Hirabayashi, H. Tsukamura, K. I. Maeda

    Journal of Neuroendocrinology   Vol. 28 ( 10 )   2016.10

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    © 2016 British Society for Neuroendocrinology Rodents show apparent sex differences in their sexual behaviours. The present study used Kiss1 knockout (KO) rats to evaluate the role of kisspeptin in the defeminisation/masculinisation of the brain mechanism that controls sexual behaviours. Castrated adult Kiss1 KO males treated with testosterone showed no male sexual behaviours but demonstrated the oestrogen-induced lordosis behaviours found in wild-type females. The sizes of some of the sexual dimorphic nuclei of Kiss1 KO male rats are similar to those of females. Plasma testosterone levels at embryonic day 18 and postnatal day 0 (PND0) in Kiss1 KO males were high, similar to wild-type males, indicating that perinatal testosterone is secreted in a kisspeptin-independent manner. Long-term exposure to testosterone from peripubertal to adult periods restored mounts and intromissions in KO males, suggesting that kisspeptin-dependent peripubertal testosterone secretion is required to masculinise the brain mechanism. This long-term testosterone treatment failed to abolish lordosis behaviours in KO males, whereas kisspeptin replacement at PND0 reduced lordosis quotients in Kiss1 KO males but not in KO females. These results suggest that kisspeptin itself is required to defeminise behaviour in the perinatal period, in cooperation with testosterone. Oestradiol benzoate treatment at PND0 suppressed lordosis quotients in Kiss1 KO rats, indicating that the mechanisms downstream of oestradiol work properly in the absence of kisspeptin. There was no significant difference in aromatase gene expression in the whole hypothalamus between Kiss1 KO and wild-type male rats at PND0. Taken together, the present study demonstrates that both perinatal kisspeptin and kisspeptin-independent testosterone are required for defeminisation of the brain, whereas kisspeptin-dependent testosterone during peripuberty to adulthood is needed for masculinisation of the brain in male rats.

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  62. Maturation and physiology of hypothalamic regulation of the gonadal axis Reviewed

    Yoshihisa Uenoyama, Naoko Inoue, Nahoko Ieda, Vutha Pheng, Kei Ichiro Maeda, Hiroko Tsukamura

    Puberty: Physiology and Abnormalities     page: 1 - 11   2016.1

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    © Springer International Publishing Switzerland 2016. In mammals, maturation of the gonadal axis at puberty appears to be timed by an increase in tonic gonadotropin release from the anterior lobe of pituitary gland, where the synthesis and release of gonadotropins, such as the follicle-stimulating hormone and luteinizing hormone, are stimulated by the gonadotropin-releasing hormone (GnRH) released from the hypothalamus. The concept of hypothalamic regulation of the gonadal axis dates back to the middle of last century, and our understanding for the GnRH/gonadotropin-releasing system has become abundantly clearer from studies in the last few decades or so. To date, the most plausible interpretation is that KNDy neurons, which produce kisspeptin, neurokinin B, and dynorphin A, serve as a master regulator of tonic GnRH/gonadotropin release, which governs the pubertal maturation of gonadal activity, i.e., gametogenesis and steroidogenesis. Estrogen derived from the immature ovary appears to play a critical role in prepubertal restraint of kisspeptin biosynthesis and hence GnRH/gonadotropin release in rodents and sheep. Decreased sensitivity to estrogen negative feedback during the pubertal transition is likely a key event for pubertal maturation of the hypothalamic mechanism regulating GnRH and then gonadal activity. It is noteworthy that steroid dependency differs from species to species. In primates, steroid-independent inhibition is mainly underlying the prepubertal restraint of GnRH/gonadotropin-releasing system. In all mammalian species, the timing of puberty onset is dependent on body weight rather than chronological age. Thus, hypothalamic mechanisms underlying the relationship between nutritional statuses and relieving the prepubertal restraint of kisspeptin biosynthesis are still unanswered questions.

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  63. ほ乳類の性成熟を制御する脳内メカニズムの解明 Invited

    上野山賀久, 束村博子

    生物科学   Vol. 67 ( 3 ) page: 161 - 167   2016

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  64. ほ乳類の生殖機能を制御するエストロジェンのフィードバック作用を仲介する脳内メカニズム Invited

    上野山賀久,束村博子

    日本生殖内分泌学会雑誌   Vol. 21   page: 5 - 8   2016

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  65. Molecular and Epigenetic Mechanism Regulating Hypothalamic Kiss1 Gene Expression in Mammals Reviewed International journal

    Yoshihisa Uenoyama, Junko Tomikawa, Naoko Inoue, Teppei Goto, Shiori Minabe, Nahoko Ieda, Sho Nakamura, Youki Watanabe, Kana Ikegami, Fuko Matsuda, Satoshi Ohkura, Kei Ichiro Maeda, Hiroko Tsukamura

    Neuroendocrinology   Vol. 103 ( 6 ) page: 640 - 649   2016

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    © 2016 S. Karger AG, Basel. Copyright: All rights reserved. After the discovery of hypothalamic kisspeptin encoded by the Kiss1 gene, the central mechanism regulating gonadotropin- releasing hormone (GnRH) secretion, and hence gonadotropin secretion, is gradually being unraveled. This has increased our understanding of the central mechanism regulating puberty and subsequent reproductive performance in mammals. Recently, emerging evidence has indicated the molecular and epigenetic mechanism regulating hypothalamic Kiss1 gene expression. Here we compile data regarding DNA and histone modifications in the Kiss1 promoter region and provide a hypothetic scheme of the molecular and epigenetic mechanism regulating Kiss1 gene expression in two populations of hypothalamic kisspeptin neurons, which govern puberty and subsequent reproductive performance via GnRH/gonadotropin secretion.

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  66. Erratum: J Reprod Dev, Vol. 59, No. 3, p. 266-272, Dynorphin-Kappa Opioid Receptor Signaling Partly Mediates Estrogen Negative Feedback Effect on LH Pulses in Female Rats. Reviewed

    Mst Parvin Mostari, Nahoko Ieda, Chikaya Deura, Shiori Minabe, Shunji Yamada, Yoshihisa Uenoyama, Kei-Ichiro Maeda, Hiroko Tsukamura

    The Journal of reproduction and development   Vol. 62 ( 5 ) page: e1   2016

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    Figure 3(a) have been corrected.

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  67. Central estrogen action sites involved in prepubertal restraint of pulsatile luteinizing hormone release in female rats Reviewed

    Yoshihisa Uenoyama, Akira Tanaka, Kenji Takase, Shunji Yamada, Vutha Pheng, Naoko Inoue, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 61 ( 4 ) page: 351 - 359   2015.8

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    © 2015 by the Society for Reproduction and Development. The present study aimed to determine estrogen feedback action sites to mediate prepubertal restraint of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release in female rats. Wistar-Imamichi strain rats were ovariectomized (OVX) and received a local estradiol-17β (estradiol) or cholesterol microimplant in several brain areas, such as the medial preoptic area (mPOA), paraventricular nucleus, ventromedial nucleus and arcuate nucleus (ARC), at 20 or 35 days of age. Six days after receiving the estradiol microimplant, animals were bled to detect LH pulses at 26 or 41 days of age, representing the pre- or postpubertal period, respectively. Estradiol microimplants in the mPOA or ARC, but not in other brain regions, suppressed LH pulses in prepubertal OVX rats. Apparent LH pulses were found in the postpubertal period in all animals bearing estradiol or cholesterol implants. It is unlikely that pubertal changes in responsiveness to estrogen are due to a change in estrogen receptor (ER) expression, because the number of ERα-immunoreactive cells and mRNA levels of Esr1, Esr2 and Gpr30 in the mPOA and ARC were comparable between the pre- and postpubertal periods. In addition, kisspeptin or GnRH injection overrode estradiol-dependent prepubertal LH suppression, suggesting that estrogen inhibits the kisspeptin-GnRH cascade during the prepubertal period. Thus, estrogen-responsive neurons located in the mPOA and ARC may play key roles in estrogen-dependent prepubertal restraint of GnRH/LH secretion in female rats.

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  68. Pharmacological and morphological evidence of AMPK-mediated energy sensing in the lower brain stem ependymocytes to control reproduction in female rodents Reviewed International journal

    Shiori Minabe, Chikaya Deura, Kana Ikegami, Teppei Goto, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Endocrinology   Vol. 156 ( 6 ) page: 2278 - 2287   2015.6

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    Copyright © 2015 by the Endocrine Society. Ependymocytes are one of the energy-sensing cells that regulate animal reproduction through their responsiveness to changes in extracellular glucose levels and the expression of pancreatictype glucokinase and glucose transporter 2, which play a critical role in sensing blood glucose levels in pancreatic β-cells. Molecular mechanisms underlying glucose sensing in the ependymocytes remain poorly understood. The AMP-activated protein kinase (AMPK), a serine/threonine kinase highly conserved in all eukaryotic cells, has been suggested to be an intracellular fuel gauge that detects cellular energy status. The present study aims to clarify the role AMPK of the lower brainstem ependymocytes has in sensing glucose levels to regulate reproductive functions. First, we will show that administration of 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, an AMPK activator, into the 4th ventricle suppressed pulsatile LH release in female rats. Second, we will demonstrate the presence of AMPK catalytic subunit immunoreactivities in the rat lower brainstem ependymocytes. Third, transgenic mice were generated to visualize the ependymocytes with Venus, a green fluorescent protein, expressed under the control of the mouse vimentin promoter for further in vitro study. The Venus-labeled ependymocytes taken from the lower brainstem of transgenic mice revealed that AMPK activation by 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside, an AMPK activator, increased in vitro intracellular calcium concentrations. Taken together, malnutrition-induced AMPK activation of ependymocytes of the lower brainstem might be involved in suppression of GnRH/LH release and then gonadal activities.

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  69. Lack of pulse and surge modes and glutamatergic stimulation of luteinising hormone release in Kiss1 knockout rats Reviewed

    Y. Uenoyama, S. Nakamura, Y. Hayakawa, K. Ikegami, Y. Watanabe, C. Deura, S. Minabe, J. Tomikawa, T. Goto, N. Ieda, N. Inoue, M. Sanbo, C. Tamura, M. Hirabayashi, K. I. Maeda, H. Tsukamura

    Journal of Neuroendocrinology   Vol. 27 ( 3 ) page: 187 - 197   2015.3

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    © 2015 British Society for Neuroendocrinology. Kisspeptin, encoded by the Kiss1 gene, has attracted attention as a key candidate neuropeptide in controlling puberty and reproduction via regulation of gonadotrophin-releasing hormone (GnRH) secretion in mammals. Pioneer studies with Kiss1 or its cognate receptor Gpr54 knockout (KO) mice showed the indispensable role of kisspeptin-GPR54 signalling in the control of animal reproduction, although detailed analyses of gonadotrophin secretion, especially pulsatile and surge-mode of luteinising hormone (LH) secretion, were limited. Thus, in the present study, we have generated Kiss1 KO rats aiming to evaluate a key role of kisspeptin in governing reproduction via pulse and surge modes of GnRH/LH secretion. Kiss1 KO male and female rats showed a complete suppression of pulsatile LH secretion, which is responsible for folliculogenesis and spermatogenesis, and an absence of puberty and atrophic gonads. Kiss1 KO female rats showed no spontaneous LH/follicle-stimulating hormone surge and an oestrogen-induced LH surge, suggesting that the GnRH surge generation system, which is responsible for ovulation, does not function without kisspeptin. Furthermore, challenge of major stimulatory neurotransmitters, such as monosodium glutamate, NMDA and norepinephrine, failed to stimulate LH secretion in Kiss1 KO rats, albeit they stimulated LH release in wild-type controls. Taken together, the results of the present study confirm that kisspeptin plays an indispensable role in generating two modes (pulse and surge) of GnRH/gonadotrophin secretion to regulate puberty onset and normal reproductive performance. In addition, the present study suggests that kisspeptin neurones play a critical role as a hub integrating major stimulatory neural inputs to GnRH neurones, using newly established Kiss1 KO rats, which serve as a useful model for detailed analysis of hormonal profiles.

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  70. Identification of hypothalamic arcuate nucleus-specific enhancer region of Kiss1 gene in mice Reviewed International journal

    Teppei Goto, Junko Tomikawa, Kana Ikegami, Shiori Minabe, Hitomi Abe, Tatsuya Fukanuma, Takuya Imamura, Kenji Takase, Makoto Sanbo, Koichi Tomita, Masumi Hirabayashi, Kei Ichiro Maeda, Hiroko Tsukamura, Yoshihisa Uenoyama

    Molecular Endocrinology   Vol. 29 ( 1 ) page: 121 - 129   2015.1

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    © 2015 by the Endocrine Society. Pulsatile secretion of GnRH plays a pivotal role in follicular development via stimulating tonic gonadotropin secretion in mammals. Kisspeptin neurons, located in the arcuate nucleus (ARC), are considered to be an intrinsic source of the GnRH pulse generator. The present study aimed to determine ARC-specific enhancer(s) of the Kiss1 gene by an in vivo reporter assay. Three green fluorescent protein (GFP) reporter constructs (long, medium length, and short) were generated by insertion of GFP cDNA at the Kiss1 locus. Transgenic female mice bearing the long and mediumlength constructs showed apparent GFP signals in kisspeptin-immunoreactive cells in both the ARC and anteroventral periventricular nucleus, in which another population of kisspeptin neurons are located. On the other hand, transgenic mice bearing 5′-truncated short construct showed few GFP signals in the ARC kisspeptin-immunoreactive cells, whereas they showed colocalization of GFPand kisspeptin-immunoreactivities in the anteroventral periventricular nucleus. In addition, chromatin immunoprecipitation and chromosome conformation capture assays revealed recruitment of unoccupied estrogen receptor-α in the 5′-upstream region and intricate chromatin loop formation between the 5′-upstream and promoter regions of Kiss1 locus in the ARC. Taken together, the present results indicate that 5′-upstream region of Kiss1 locus plays a critical role in Kiss1 gene expression in an ARC-specific manner and that the recruitment of estrogen receptor-α and formation of a chromatin loop between the Kiss1 promoter and the 5′ enhancer region may be required for the induction of ARC-specific Kiss1 gene expression. These results suggest that the 5′-upstream region of Kiss1 locus functions as an enhancer for ARC Kiss1 gene expression in mice.

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  71. The Luteinising Hormone Surge-Generating System is Functional in Male Goats as in Females: Involvement of Kisspeptin Neurones in the Medial Preoptic Area Reviewed

    F. Matsuda, K. Nakatsukasa, Y. Suetomi, Y. Naniwa, D. Ito, N. Inoue, Y. Wakabayashi, H. Okamura, K. I. Maeda, Y. Uenoyama, H. Tsukamura, S. Ohkura

    Journal of Neuroendocrinology   Vol. 27 ( 1 ) page: 57 - 65   2015.1

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    © 2014 British Society for Neuroendocrinology. A luteinising hormone (LH) surge is fundamental to the induction of ovulation in mammalian females. The administration of a preovulatory level of oestrogen evokes an LH surge in ovariectomised females, whereas the response to oestrogen in castrated males differs among species; namely, the LH surge-generating system is sexually differentiated in some species (e.g. rodents and sheep) but not in others (e.g. primates). In the present study, we aimed to determine whether there is a functional LH surge-generating system in male goats, and whether hypothalamic kisspeptin neurones in male goats are involved in the regulation of surge-like LH secretion. By i.v. infusion of oestradiol (E2; 6 μg/h) for 16 h, a surge-like LH increase occurred in both castrated male and ovariectomised female goats, although the mean peak LH concentration was lower and the mean peak of the LH surge was later in males compared to females. Dual staining with KISS1 in situ hybridisation and c-Fos immunohistochemistry revealed that E2 treatment significantly increased c-Fos expression in the medial preoptic area (mPOA) KISS1 cells in castrated males, as well as ovariectomised females. By contrast, dual-labelled cells were scarcely detected in the arcuate nucleus (ARC) after E2 treatment in both sexes. These data suggest that kisspeptin neurones in the mPOA, but not those in the ARC, are involved in the induction of surge-like LH secretion in both male and female goats.

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  72. Oestrogen-induced activation of preoptic kisspeptin neurones may be involved in the luteinising hormone surge in male and female Japanese monkeys Reviewed

    Y. Watanabe, Y. Uenoyama, J. Suzuki, K. Takase, Y. Suetomi, S. Ohkura, N. Inoue, K. I. Maeda, H. Tsukamura

    Journal of Neuroendocrinology   Vol. 26 ( 12 ) page: 909 - 917   2014.12

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    © 2014 British Society for Neuroendocrinology. The oestrogen-induced luteinising hormone (LH) surge is evident in male primates, including humans, whereas male rodents never show the LH surge, even when treated with a preovulatory level of oestrogen. This suggests that the central mechanism governing reproductive hormones in primates is different from that in rodents. The present study aimed to investigate whether male Japanese monkeys conserve a brain mechanism mediating the oestrogen-induced LH surge via activation of kisspeptin neurones. Adult male and female Japanese monkeys were gonadectomised and then were treated with oestradiol-17β for 2 weeks followed by a bolus injection of oestradiol benzoate. Both male and female monkeys showed an oestrogen-induced LH surge. In gonadectomised monkeys sacrificed just before the anticipated time of the LH surge, oestrogen treatment significantly increased the number of KISS1-expressing cells in the preoptic area (POA) and enhanced the expression of c-fos in POA KISS1-positive cells of males and females. The oestrogen treatment failed to induce c-fos expression in the arcuate nucleus (ARC) kisspeptin neurones in both sexes just prior to LH surge onset. Thus, kisspeptin neurones in the POA but not in the ARC might be involved in the positive-feedback action of oestrogen that induces LH surge in male Japanese monkeys, as well as female monkeys. The present results indicate that oestrogen-induced activation of POA kisspeptin neurones may contribute to the LH surge generation in both sexes. The conservation of the LH surge generating system found in adult male primates, unlike rodents, could be a result of the capability of oestrogen to induce POA kisspeptin expression and activation.

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  73. Design and synthesis of fluorescent probes for GPR54 Reviewed International journal

    Masato Kaneda, Ryosuke Misu, Hiroaki Ohno, Akira Hirasawa, Nahoko Ieda, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Shinya Oishi, Nobutaka Fujii

    Bioorganic and Medicinal Chemistry   Vol. 22 ( 13 ) page: 3325 - 3330   2014.7

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    Kisspeptins are neuropeptides that induce the secretion of gonadotropin-releasing hormone via the activation of the cognate receptor, G-protein coupled receptor 54 (GPR54). The kisspeptin-GPR54 axis is associated with the onset of puberty and the maintenance of the reproductive system. In this study, several fluorescent probes have been designed and synthesized for rat GPR54 through the modification of the N-terminus of rat kisspeptins to allow for the visualization of the expression and localization of kisspeptin receptor(s) in living cells and native tissues. The tetramethylrhodamine (TMR) and rhodamine green (RG)-labeled kisspeptins exhibited good binding and agonistic activities towards GPR54, and the results of the application studies demonstrated that these fluorescent probes could be used effectively for the detection of GPR54 receptors in flow cytometry and confocal microscopy experiments. © 2014 Elsevier Ltd. All rights reserved.

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  74. KISS1 gene expression in the developing brain of female pigs in pre- and peripubertal periods Reviewed

    Nahoko Ieda, Yoshihisa Uenoyama, Yoko Tajima, Tomoko Nakata, Masatoshi Kano, Yousuke Naniwa, Youki Watanabe, Shiori Minabe, Junko Tomikawa, Naoko Inoue, Fuko Matsuda, Satoshi Ohkura, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 60 ( 4 ) page: 312 - 316   2014.6

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    ©2014 by the Society for Reproduction and Development. Puberty is associated with an increase in gonadotropin secretion as a result of an increase in gonadotropin-releasing hormone (GnRH) secretion. Kisspeptin is considered to play a key role in puberty onset in many mammalian species, including rodents, ruminants and primates. The present study aimed to determine if changes in hypothalamic expression of the KISS1 gene, encoding kisspeptin, are associated with the onset of puberty in pigs. The animals (n=4 in each group) were perfused with 4% paraformaldehyde at 0, 1, 2, 3 and 4 months old, as prepubertal stages, and at 5 months old, as the peripubertal stage, following each blood sampling. KISS1 gene expressions in coronal sections of brains were visualized by in situ hybridization. Plasma luteinizing hormone (LH) was measured by radioimmunoassay. KISS1 mRNA signals were observed in the arcuate nucleus (ARC) at all ages examined without any significant difference in the number of KISS1-expressing cells, indicating that the KISS1 gene is constantly expressed in the ARC throughout pubertal development in pigs. The plasma LH concentration was the highest in 0-month-old piglets and significantly decreased in the 1- and 2 month-old groups (P<0.05), suggesting a developing negative feedback mechanism affecting gonadotropin release during the prepubertal period. Considering the potent stimulating effect of kisspeptin on gonadotropin release in prepubertal pigs, kisspeptin secretion rather than kisspeptin synthesis may be responsible for the onset of puberty in pigs.

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  75. KNDy neuron as a gatekeeper of puberty onset International journal

    Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Obstetrics and Gynaecology Research   Vol. 40 ( 6 ) page: 1518 - 1526   2014.6

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    Hypothalamo-pituitary-gonadal axis has been recognized as a functional unit orchestrating reproductive performance in mammals. The mechanism governing puberty onset, however, is still one of the great mysteries of biology. The present article reviews previous studies over the last century, which gradually elucidated the brain mechanism controlling puberty onset in mammals along with the discovery of gonadotrophins and the gonadotrophin-releasing hormone and the establishment of the concept for the hypothalamo-pituitary-gonadal axis. The discovery of kisspeptin and subsequent progress of neuroendocrinology in the last decade has resulted in much greater understanding of the way the brain governs puberty onset in mammals. © 2014 The Authors. Journal of Obstetrics and Gynaecology Research © 2014 Japan Society of Obstetrics and Gynecology.

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  76. The LH surge-generating system is functional in male goats as in females: involvement of kisspeptin neurones in the medial preoptic area. Reviewed

    Matsuda, F., Nakatsukasa, K., Suetomi, Y., Naniwa, Y., Ito, D., Inoue, N., Wakabayashi, Y., Okamura, H., Maeda, K.I., Uenoyama, Y., Tsukamura, H., Ohkura, S.

    J Neuroendocrinol     2014

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    DOI: doi: 10.1111/jne.12235.

  77. Effects of full-length kisspeptin administration on follicular development in Japanese black beef cows Reviewed

    Yousuke Naniwa, Keisuke Nakatsukasa, Shohei Setsuda, Shinya Oishi, Nobutaka Fujii, Fuko Matsuda, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Satoshi Ohkura

    Journal of Reproduction and Development   Vol. 59 ( 6 ) page: 588 - 594   2013.12

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    Kisspeptin is a key molecule that stimulates gonadotropin secretion via release of gonadotropin-releasing hormone (GnRH). In the present study, our aim was to investigate whether kisspeptin has stimulatory effects on follicular development via GnRH/gonadotropin secretion in cows. Japanese Black beef cows were intravenously injected with full-length bovine kisspeptin [Kp-53 (0.2 or 2 nmol/kg)] or vehicle 5 days after they exhibited standing estrus (Day 0). In cows injected with Kp-53 at 2 nmol/kg, the follicular sizes of the first dominant follicles increased on Day 6 and thereafter. Ovulation of the first dominant follicle occurred in 1 out of 4 cows treated with Kp-53 at 2 nmol/kg. Injection of Kp-53 at 2 nmol/kg increased the concentration of plasma luteinizing hormone (LH) but not follicle-stimulating hormone, over a 4-h period following injection in all cows. The present study suggests that administration of full-length kisspeptin causes LH secretion, which is sustained for a few hours, and it is capable of stimulating follicular development and/or ovulation. © 2013 by the Society for Reproduction and Development.

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  78. Microarray analysis of perinatal-estrogen-induced changes in gene expression related to brain sexual differentiation in mice Reviewed International journal

    Mototsugu Sakakibara, Yoshihisa Uenoyama, Shiori Minabe, Youki Watanabe, Chikaya Deura, Sho Nakamura, Genki Suzuki, Kei Ichiro Maeda, Hiroko Tsukamura

    PLoS ONE   Vol. 8 ( 11 ) page: e79437   2013.11

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    Sexual dimorphism of the behaviors or physiological functions in mammals is mainly due to the sex difference of the brain. A number of studies have suggested that the brain is masculinized or defeminized by estradiol converted from testicular androgens in perinatal period in rodents. However, the mechanisms of estrogen action resulting in masculinization/defeminization of the brain have not been clarified yet. The large-scale analysis with microarray in the present study is an attempt to obtain the candidate gene(s) mediating the perinatal estrogen effect causing the brain sexual differentiation. Female mice were injected with estradiol benzoate (EB) or vehicle on the day of birth, and the hypothalamus was collected at either 1, 3, 6, 12, or 24 h after the EB injection. More than one hundred genes down-regulated by the EB treatment in a biphasic manner peaked at 3 h and 12-24 h after the EB treatment, while forty to seventy genes were constantly up-regulated after it. Twelve genes, including Ptgds, Hcrt, Tmed2, Klc1, and Nedd4, whose mRNA expressions were down-regulated by the neonatal EB treatment, were chosen for further examination by semiquantitative RT-PCR in the hypothalamus of perinatal intact male and female mice. We selected the genes based on the known profiles of their potential roles in brain development. mRNA expression levels of Ptgds, Hcrt, Tmed2, and Nedd4 were significantly lower in male mice than females at the day of birth, suggesting that the genes are down-regulated by estrogen converted from testicular androgen in perinatal male mice. Some genes, such as Ptgds encoding prostaglandin D2 production enzyme and Hcrt encording orexin, have been reported to have a role in neuroprotection. Thus, Ptgds and Hcrt could be possible candidate genes, which may mediate the effect of perinatal estrogen responsible for brain sexual differentiation. © 2013 Sakakibara et al.

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  79. Molecular cloning and identification of the transcriptional regulatory domain of the goat neurokinin B gene TAC3 Reviewed

    Yuta Suetomi, Fuko Matsuda, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura, Satoshi Ohkura

    Journal of Reproduction and Development   Vol. 59 ( 5 ) page: 463 - 469   2013.10

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    Neurokinin B (NKB), encoded by TAC3, is thought to be an important accelerator of pulsatile gonadotropinreleasing hormone release. This study aimed to clarify the transcriptional regulatory mechanism of goat TAC3. First, we determined the full-length mRNA sequence of goat TAC3 from the hypothalamus to be 820 b, including a 381 b coding region, with the putative transcription start site located 143-b upstream of the start codon. The deduced amino acid sequence of NKB, which is produced from preproNKB, was completely conserved among goat, cattle, and human. Next, we cloned 5'-upstream region of goat TAC3 up to 3400 b from the translation initiation site, and this region was highly homologous with cattle TAC3 (89%). We used this goat TAC3 5'-upstream region to perform luciferase assays. We created a luciferase reporter vector containing DNA constructs from-2706,-1837,-834,-335, or-197 to +166 bp (the putative transcription start site was designated as +1) of goat TAC3 and these were transiently transfected into mouse hypothalamus-derived N7 cells and human neuroblastoma-derived SK-N-AS cells. The luciferase activity gradually increased with the deletion of the 5'-upstream region, suggesting that the transcriptional suppressive region is located between-2706 and-336 bp and that the core promoter exists downstream of-197 bp. Estradiol treatment did not lead to significant suppression of luciferase activity of any constructs, suggesting the existence of other factor(s) that regulate goat TAC3 transcription. © 2013 by the Society for Reproduction and Development.

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  80. Chronic peripheral administration of kappa-opioid receptor antagonist advances puberty onset associated with acceleration of pulsatile luteinizing hormone secretion in female rats Reviewed

    Tatsuo Nakahara, Yoshihisa Uenoyama, Akira Iwase, Shinya Oishi, Sho Nakamura, Shiori Minabe, Youki Watanabe, Chikaya Deura, Taro Noguchi, Nobutaka Fujii, Fumitaka Kikkawa, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 59 ( 5 ) page: 479 - 484   2013.10

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    Puberty in mammals is timed by an increase in gonadotropin-releasing hormone (GnRH) secretion. Previous studies have shown involvement of the two neuropeptides, kisspeptin and neurokinin B (NKB), in controlling puberty onset. Little is known about the role of the other key neuropeptide, dynorphin, in controlling puberty onset, although these three neuropeptides colocalize in the arcuate kisspeptin neurons. The arcuate kisspeptin neuron, which is also referred to as the KNDy neuron, has recently been considered to play a role as an intrinsic source of the GnRH pulse generator. The present study aimed to determine if attenuation of inhibitory dynorphin-kappa-opioid receptor (KOR) signaling triggers the initiation of puberty in normal developing female rats. The present study also determined if stimulatory NKB-neurokinin 3 receptor (NK3R) signaling advances puberty onset. Female Wistar-Imamichi rats were weaned and intraperitoneally implanted with osmotic minipumps filled with nor-binaltorphimine (nor-BNI), a KOR antagonist, or senktide, a NK3R agonist, at 20 days of age. Fourteen days of intraperitoneal infusion of nor-BNI or senktide advanced puberty onset, manifested as vaginal opening and the first vaginal estrus in female rats. Frequent blood sampling showed that nor-BNI significantly increased luteinizing hormone (LH) pulse frequency at 29 days of age compared with vehicle-treated controls. Senktide tended to increase this frequency, but its effect was not statistically significant. The present results suggest that the inhibitory input of dynorphin- KOR signaling plays a role in the prepubertal restraint of GnRH/LH secretion in normal developing female rats and that attenuation of dynorphin-KOR signaling and increase in NKB-NK3R signaling trigger the onset of puberty in female rats. © 2013 by the Society for Reproduction and Development.

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  81. Different critical perinatal periods and hypothalamic sites of oestradiol action in the defeminisation of luteinising hormone surge and lordosis capacity in the rat Reviewed

    M. Sakakibara, C. Deura, S. Minabe, Y. Iwata, Y. Uenoyama, K. I. Maeda, H. Tsukamura

    Journal of Neuroendocrinology   Vol. 25 ( 3 ) page: 251 - 259   2013.3

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    Female rats show a gonadotrophin-releasing hormone (GnRH)/luteinising hormone (LH) surge in the presence of a preovulatory level of oestrogen, whereas males do not because of brain defeminisation during the developmental period by perinatal oestrogen converted from androgen. The present study aimed to identify the site(s) of oestrogen action and the critical period for defeminising the mechanism regulating the GnRH/LH surge. Animals given perinatal treatments, such as steroidal manipulations, brain local implantation of oestradiol (E2) or administration of an NMDA antagonist, were examined for their ability to show an E2-induced LH surge at adulthood. Lordosis behaviour was examined to compare the mechanisms defeminising the GnRH/LH surge and sexual behaviour. A single s.c. oestradiol-benzoate administration on either the day before birth (E21), the day of birth (D0) or day 5 (D5) postpartum completely abolished the E2-induced LH surge at adulthood in female rats, although the same treatment did not inhibit lordosis. Perinatal castration on E21 or D0 partially rescued the E2-induced LH surge in genetically male rats, whereas castration from E21 to D5 totally rescued lordosis. Neonatal E2 implantation in the anterior hypothalamus including the anteroventral periventricular nucleus (AVPV)/preoptic area (POA) abolished the E2-induced LH surge in female rats, whereas E2 implantation in the mid and posterior hypothalamic regions had no inhibitory effect on the LH surge. Lordosis was not affected by neonatal E2 implantation in any hypothalamic regions. In male rats, neonatal NMDA antagonist treatment rescued lordosis but not the LH surge. Taken together, these results suggest that an anterior hypothalamic region such as the AVPV/POA region is a perinatal site of oestrogen action where the GnRH/LH regulating system is defeminised to abolish the oestrogen-induced surge. The mechanism for defeminisation of the GnRH/LH surge system might be different from that of sexual behaviour, in terms of the site(s) of oestrogen action and critical period, as well as the neurotransmitter system involved. © 2012 British Society for Neuroendocrinology.

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  82. Dynorphin-Kappa opioid receptor signaling partly mediates estrogen negative feedback effect on LH pulses in female rats Reviewed

    Mst Parvin Mostari, Nahoko Ieda, Chikaya Deura, Shiori Minabe, Shunji Yamada, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 59 ( 3 ) page: 266 - 272   2013

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    Accumulating evidence suggests that the arcuate nucleus (ARC) kisspeptin/neurokinin B (NKB)/dynorphin (KNDy) neurons play a role in estrogen negative feedback action on pulsatile gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release. The present study aimed to determine if dynorphin (Dyn) is involved in estrogen negative feedback on pulsatile GnRH/LH release. The effect of the injection of nor-binaltorphimine (nor-BNI), a kappa-opioid receptor (KOR) antagonist, into the third cerebroventricle (3V) on LH pulses was determined in ovariectomized (OVX) adult female rats with/without replacement of negative feedback levels of estradiol (low E2). The mean LH concentrations and baseline levels of LH secretion in nor-BNI-injected, low E2-treated rats were significantly higher compared with vehicle-treated controls. On the other hand, the nor-BNI treatment failed to affect any LH pulse parameters in OVX rats without low E2 treatment. These results suggest that Dyn is involved in the estrogen negative feedback regulation of pulsatile GnRH/LH release. The low E2 treatment had no significant effect on the numbers of ARC Pdyn (Dyn gene)-,Kiss1- and Tac2 (NKB gene)-expressing cells. The treatment also did not affect mRNA levels of Pdyn and Oprk1 (KOR gene) in the ARC-median eminence region, but significantly increased the ARC kisspeptin immunoreactivity. These findings suggest that the negative feedback level of estrogen suppresses kisspeptin release from the ARC KNDy neurons through an unknown mechanism without affecting the Dyn and KOR expressions in the ARC. Taken together, the present result suggests that Dyn-KOR signaling is a part of estrogen negative feedback action on GnRH/LH pulses by reducing the kisspeptin release in female rats. © 2013 by the Society for Reproduction and Development.

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  83. Epigenetic regulation of kisspeptin neurons mediating estrogen-feedback action on GnRH release Reviewed

    Hiroko Tsukamura, Junko Tomikawa, Yoshihisa Uenoyama, Kei-ichiro Maeda

    JOURNAL OF PHYSIOLOGICAL SCIENCES   Vol. 63   page: S104 - S104   2013

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  84. Kisspeptin and GnRH pulse generation Reviewed International journal

    Hiroaki Okamura, Hiroko Tsukamura, Satoshi Ohkura, Yoshihisa Uenoyama, Yoshihiro Wakabayashi, Kei Ichiro Maeda

    KISSPEPTIN SIGNALING IN REPRODUCTIVE BIOLOGY Advances in Experimental Medicine and Biology   Vol. 784   page: 297 - 323   2013

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    The reproductive neuropeptide gonadotropin-releasing hormone (GnRH) has two modes of secretion. Besides the surge mode, which induces ovulation in females, the pulse mode of GnRH release is essential to cause various reproductive events in both sexes, such as spermatogenesis, follicular development, and sex steroid synthesis. Some environmental cues control gonadal activities through modulating GnRH pulse frequency. Researchers have looked for the anatomical location of the mechanism generating GnRH pulses, the GnRH pulse generator, in the brain, because an artificial manipulation of GnRH pulse frequency is of therapeutic importance to stimulate or suppress gonadal activity. Discoveries of kisspeptin and, consequently, KNDy (kisspeptin/neurokinin B/dynorphin) neurons in the hypothalamus have provided a clue to the possible location of the GnRH pulse generator. Our analyses of hypothalamic multiple-unit activity revealed that KNDy neurons located in the hypothalamic arcuate nucleus might play a central role in the generation of GnRH pulses in goats, and perhaps other mammalian species. This chapter further discusses the possible mechanisms for GnRH pulse generation. © Springer Science+Business Media, LLC 2013.

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  85. Indispensable role of kisspeptin in controlling gonadotropin-releasing hormone release in mammals Reviewed

    Yoshihisa Uenoyama, Sho Nakamura, Hiroko Tsukamura, Kei-ichiro Maeda

    JOURNAL OF PHYSIOLOGICAL SCIENCES   Vol. 63   page: S12 - S12   2013

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  86. Oestrogen-Dependent Suppression of Pulsatile Luteinising Hormone Secretion and Kiss1 mRNA Expression in the Arcuate Nucleus During Late Lactation in Rats Reviewed

    S. Yamada, Y. Uenoyama, C. Deura, S. Minabe, Y. Naniwa, K. Iwata, M. Kawata, K. I. Maeda, H. Tsukamura

    Journal of Neuroendocrinology   Vol. 24 ( 9 ) page: 1234 - 1242   2012.9

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    Follicular development and ovulation are strongly suppressed during lactation in mammals via a profound suppression of gonadotrophin secretion. The present study aimed to examine the role of oestrogen feedback action in suppressing luteinising hormone (LH) secretion and hypothalamic kisspeptin expression during the latter half of lactation. Plasma LH concentrations kept at low levels throughout the lactating period in intact and oestrogen-replaced ovariectomised (OVX) lactating rats, whereas plasma LH concentrations gradually elevated from day 10 postpartum in lactating OVX rats. OVX lactating rats showed frequent LH pulses at late lactation, although the LH pulses were significantly inhibited by an oestrogen replacement, which is much less effective on LH release in nonlactating rats. Oestrogen replacement in lactating OVX rats significantly reduced the number of Kiss1 mRNA-expressing cells in the arcuate nucleus (ARC) at late lactation, although the same oestrogen treatment did not affect the number of Kiss1-expressing cells in nonlactating controls. Exogenous kisspeptin challenge (0.2nmol) into the third cerebroventricle significantly increased LH secretion in lactating OVX, lactating OVX+subcutaneous 17β-oestradiol and intact lactating rats at day 16 postpartum. These results suggest that LH pulse suppression during late lactation could be a result of the enhanced oestrogen-dependent suppression of ARC kisspeptin expression. © 2012 The Authors. Journal of Neuroendocrinology © 2012 British Society for Neuroendocrinology.

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  87. Central distribution of kiss2 neurons and peri-pubertal changes in their expression in the brain of male and female red seabream pagrus major Reviewed International journal

    Yuki Shimizu, Junko Tomikawa, Keisuke Hirano, Yoko Nanikawa, Yasuhisa Akazome, Shinji Kanda, Yukinori Kazeto, Koichi Okuzawa, Yoshihisa Uenoyama, Satoshi Ohkura, Hiroko Tsukamura, Kei ichiro Maeda, Koichiro Gen, Yoshitaka Oka, Naoyuki Yamamoto

    General and Comparative Endocrinology   Vol. 175 ( 3 ) page: 432 - 442   2012.2

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    kisspeptins that are encoded by kiss1 gene are now considered the key regulator of reproduction from a number of studies in mammals. In most vertebrates, a paralogue of kiss1, called kiss2, is also present, and the functional significance of kisspeptins is not known precisely. In the present study, we have cloned kiss2 from a perciform teleost, the red seabream Pagrus major. The amino acid sequence deduced from the red seabream kiss2 contained a highly conserved 10-amino-acid residue, Kiss2(10) or kp-10. A kiss1-like transcript was also identified, but it appears to be non-functional due to the presence of a "premature" stop codon. Neurons that express kiss2 mRNA were distributed in the dorsal (NRLd) and ventral (NRLv) parts of nucleus recessi lateralis in the hypothalamus. In some fish a few kiss2-expressing neurons were detected in the preoptic area and nucleus ventralis tuberis. The number of kiss2-expressing neurons in the NRLd was larger during the first spawning season in both males and females compared with fish in the post-spawning periods. In males the number of kiss2 neurons in the NRLd of maturing fish was also larger than those in the post-spawning periods. In males the number of kiss2 neurons in the NRLv showed a similar pattern of changes to that of NRLd, while significant changes were not detected for females. The numbers of gonadotropin-releasing hormone 1 (GnRH1)-immunoreactive neurons in the preoptic area showed a similar pattern of change as those of kiss2 cells of the NRLd in both males and females (and also the NRLv in males). These results are in good agreement with the hypothesis that kiss2 neurons are involved in pubertal processes via regulatory influences on GnRH1 neurons in red seabream. © 2011 Elsevier Inc.

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  88. Epigenetic regulation of Kiss1 gene expression mediating estrogen-positive feedback action in themouse brain. Reviewed

    Tomikawa, J., Uenoyama, Y., Ozawa M., Fukanuma, T., Takase, K., Goto, T., Abe, H., Ieda, N., Minabe, S., Deura, C., Inoue, N., Sanbo, M., Tomita, K., Hirabayashi, M., Tanaka, S., Imamura, T., Okamura, H., Maeda, K.-I., Tsukamura, H.

    Proceedings of National Academy of Sciences of the United States of America     page: E1294-E1301   2012

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  89. Kisspeptin neurons mediate reflex ovulation in the musk shrew (Suncus murinus) Reviewed International journal

    Naoko Inoue, Karin Sasagawa, Kotaro Ikai, Yuki Sasaki, Junko Tomikawa, Shinya Oishi, Nobutaka Fujii, Yoshihisa Uenoyama, Yasushige Ohmori, Naoyuki Yamamoto, Eiichi Hondo, Kei Ichiro Maeda, Hiroko Tsukamura

    Proceedings of the National Academy of Sciences of the United States of America   Vol. 108 ( 42 ) page: 17527 - 17532   2011.10

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    The present study investigated whether kisspeptin-G protein-coupled receptor 54 (GPR54) signaling plays a role in mediating mating- induced ovulation in the musk shrew (Suncus murinus), a reflex ovulator. For this purpose, we cloned suncus Kiss1 and Gpr54 cDNA from the hypothalamus and found that suncus kisspeptin (sKp) consists of 29 amino acid residues (sKp-29). Injection of exogenous sKp-29 mimicked the mating stimulus to induce follicular maturation and ovulation. Administration of several kisspeptins and GPR54 agonists also induced presumed ovulation in a dose-dependent manner, and Gpr54 mRNA was distributed in the hypothalamus, showing that kisspeptins induce ovulation through binding to GPR54. The sKp-29-induced ovulation was blocked completely by pretreatment with a gonadotropin-releasing hormone (GnRH) antagonist, suggesting that kisspeptin activates GnRH neurons to induce ovulation in the musk shrew. In addition, in situ hybridization revealed that Kiss1-expressing cells are located in the medial preoptic area (POA) and arcuate nucleus in the musk shrew hypothalamus. The number of Kiss1-expressing cells in the POA or arcuate nucleus was up-regulated or downregulated by estradiol, suggesting that kisspeptin neurons in these regions were the targets of the estrogen feedback action. Finally, mating stimulus largely induced c-Fos expression in Kiss1-positive cells in the POA, indicating that the mating stimulus activates POA kisspeptin neurons to induce ovulation. Taken together, these results indicate that kisspeptin-GPR54 signaling plays a role in the induction of ovulation in the musk shrew, a reflex ovulator, as it does in spontaneous ovulators.

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  90. Single-stranded noncoding RNAs mediate local epigenetic alterations at gene promoters in rat cell lines Reviewed International journal

    Junko Tomikawa, Hiroko Shimokawa, Masahiro Uesaka, Naoki Yamamoto, Yuji Mori, Hiroko Tsukamura, Kei Ichiro Maeda, Takuya Imamura

    Journal of Biological Chemistry   Vol. 286 ( 40 ) page: 34788 - 34799   2011.10

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    Agrowing number of noncoding RNAs (ncRNAs) are thought to be involved in sequence-specific alterations of epigenetic processes, mostly causing gene repression. In this study, promoterassociated ncRNAs (pancRNAs >200 nucleotides in size) that were endogenously generated from the sense strand at Map2b, antisense strand at Nefl, and both strands at Vim were investigated regarding their epigenetic potential as positive or negative regulators in rat pheochromocytoma (PC12) and fibroblast (normal rat kidney) cell lines. The respective antisense pancRNAs were associated with several active chromatin marks at the Nefl and Vim promoters. Forced expression of fragments expressing the antisense pancRNAs caused sequence-specific DNA demethylation, whereas a decrease of expression induced methylation of the same sequences. In contrast, perturbing the expression of the two sense pancRNAs did not change the DNA methylation status. These results suggest that a fraction of naturally occurring ncRNAs acts in cis as a single-stranded form and that the transcriptional orientation of pancRNA is important for the establishment of sequence-specific epigenetic modifications consistent with open chromatin structure. © 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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  91. Analysis of pulsatile and surge-like luteinizing hormone secretion with frequent blood sampling in female mice Reviewed

    Shiori Minabe, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 57 ( 5 ) page: 660 - 664   2011.10

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    Mice have become more important as genetically-modified model animals for analysis of physiological functions. The establishment of a frequent blood sampling system in conscious mice would provide a powerful tool for a better and more detailed understanding of the physiological status of circulating hormonal changes, such as pulse or surge modes of luteinizing hormone (LH) secretion. Frequent blood sampling, however, is considered problematic in mice because of the limited blood volume for their small body size. The present study, therefore, aims to establish a blood sampling protocol to determine the pulse and surge modes of LH secretion using intra-atrial cannulation and frequent blood sampling in free-moving conscious mice. Ovariectomized mice were bled every 3 min for 1.5 h to detect LH pulses. Blood glucose levels, an indicator of stress, were kept constant throughout the 1.5-h sampling period, suggesting that sampling can be performed under stress-free conditions. Obvious LH pulses were observed in ad lib-fed ovariectomized mice, whereas they were significantly suppressed after a 24-h fast. This indicates that the present sampling protocol is suitable for detecting physiological changes in pulsatile LH secretion. In addition, 1-h-interval blood collections in proestrous mice between 1300 and 2200 h revealed that individual preovulatory LH surges occur in the evening of proestrous days. Thus, the present study has developed a blood sampling protocol to detect individual profiles of pulse and surge modes of LH secretion in mice. © 2011 by the Society for Reproduction and Development.

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  92. Ultrastructural Evidence of Kisspeptin-Gonadotrophin-Releasing Hormone (GnRH) Interaction in the Median Eminence of Female Rats: Implication of Axo-Axonal Regulation of GnRH Release Reviewed

    Y. Uenoyama, N. Inoue, V. Pheng, T. Homma, K. Takase, S. Yamada, K. Ajiki, M. Ichikawa, H. Okamura, K. I. Maeda, H. Tsukamura

    Journal of Neuroendocrinology   Vol. 23 ( 10 ) page: 863 - 870   2011.10

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    The present study was conducted to determine the morphological and functional interaction between kisspeptin and gonadotrophin-releasing hormone (GnRH) neuronal elements at the median eminence in female rats to clarify a possibility that kisspeptin directly stimulates GnRH release at the nerve end. A dual immunoelectron microscopic study of kisspeptin and GnRH showed that the kisspeptin-immunoreactive nerve element directly abutted the GnRH-immunoreactive nerve element, although no obvious synaptic structure was found between kisspeptin and GnRH neurones in the median eminence. The current retrograde tracing study with FluoroGold (FG) indicates that kisspeptin neurones are not in contact with fenestrated capillaries because no FG signal was found in kisspeptin neurones when the FG was injected peripherally. This peripheral FG injection revealed the neuroendocrine neurones projecting to the median eminence because FG-positive GnRH neuronal cell bodies were found in the preoptic area. Synthetic rat kisspeptin (1-52)-amide stimulated GnRH release from the median eminence tissues in a dose-dependent manner. Thus, the present results suggest that kisspeptin at least partly exerts stimulatory effects on GnRH release from the neuronal terminals of GnRH neurones by axo-axonal nonsynaptic interaction in the median eminence. © 2011 The Authors. Journal of Neuroendocrinology © 2011 Blackwell Publishing Ltd.

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  93. Circadian transcriptional factor DBP regulates expression of Kiss1 in the anteroventral periventricular nucleus Reviewed International journal

    Zhifang Xu, Shigehito Kaga, Jun Tsubomizu, Jun Fujisaki, Akikazu Mochiduki, Takafumi Sakai, Hiroko Tsukamura, Kei ichiro Maeda, Kinji Inoue, Akihito A. Adachi

    Molecular and Cellular Endocrinology   Vol. 339 ( 1-2 ) page: 90 - 97   2011.6

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    The expression of Kiss1 in the anteroventral periventricular nucleus (AVPV) and its product, metastin/kisspeptin, show a circadian pattern with a peak in the evening, which shows a strong phase relationship with the time of the gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) surge in rodents. Here we report that a circadian transcriptional factor, albumin D-site binding protein (Dbp), was able to trigger mKiss1 transcription via the D-box, and this effect was combined with those of estrogen receptor α (ERα) and its ligand, estrogen. A histological study demonstrated that some cells in the AVPV co-expressed Dbp with ERα in adult female rats. Expression of ERα was not rhythmic in the AVPV, however, mRNA of Dbp in the AVPV accumulated with a robust diurnal rhythm in proestrus, but not on the first day of diestrus. Thus, these results suggest that Dbp and estrogen regulate the expression of Kiss1 in the AVPV, thereby mediating the GnRH/LH surge. © 2011 Elsevier Ireland Ltd.

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  94. Central injection of ketone body suppresses luteinizing hormone release via the catecholaminergic pathway in female rats Reviewed

    Kinuyo Iwata, Mika Kinoshita, Naoki Susaki, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 57 ( 3 ) page: 379 - 84   2011.6

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    Ketosis is found in various pathophysiological conditions, including diabetes and starvation, that are accompanied by suppression of gonadal activity. The aim of the present study was to determine the role of ketone body in the brain in regulating pulsatile luteinizing hormone (LH) secretion in female rats. Injection of 3-hydroxybutyrate (3HB), a ketone body, into the fourth cerebroventricle (4V) induced suppression of pulsatile LH secretion in a dosedependent manner in ovariectomized (OVX) rats with an estradiol (E2) implant producing diestrus plasma E2 levels. Plasma glucose and corticosterone levels increased immediately after the 4V 3HB injection, suggesting that the treatment caused a hunger response. The 3HB-induced suppression of LH pulses might be mediated by noradrenergic inputs to the hypothalamic paraventricular nucleus (PVN) because a local injection of α-methyl-p-tyrosine, a catecholamine synthesis inhibitor, into the PVN blocked 3HB-induced suppression of LH pulses and PVN noradrenaline release was increased by 4V 3HB injection in E2-primed OVX rats. These results suggest that ketone body sensed by a central energy sensor in the hindbrain may suppress gonadotropin release via noradrenergic inputs to the PVN under ketosis. © 2011 by the Society for Reproduction and Development.

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  95. Involvement of neurokinin receptors in the control of pulsatile luteinizing hormone secretion in rats Reviewed

    Ken Ichi Noritake, Toshiki Matsuoka, Tetsuya Ohsawa, Kazuhiro Shimomura, Atsushi Sanbuissho, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 57 ( 3 ) page: 409 - 415   2011.6

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    It has recently been shown that neurokinin B, a tachykinin, is associated with GnRH pulse generation in sheep and goats. The aim of the present study was to clarify the role of tachykinin receptors in the control of LH secretion in rats. To this end, we evaluated the effect of CS-003, an antagonist for all three neurokinin receptors (NK1, NK2 and NK3 receptors), on pulsatile LH secretion in both sexes of rats with different routes of administration. Both oral and third ventricular administration of CS-003 suppressed LH secretion in both sexes of gonadectomized animals. Furthermore, intact male rats with oral administration of CS-003 showed decreased serum testosterone levels, which might be due to suppressed LH secretion. None of the three subtype-specific neurokinin receptor antagonists showed a significant effect on LH secretion in ovariectomized rats when each antagonist was singly administered. The present results suggest that neurokinins play a role in the control of pulsatile GnRH/LH secretion via multiple neurokinin receptors in both male and female rats. © 2011 by the Society for Reproduction and Development.

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  96. Testicular toxicity induced by a triple neurokinin receptor antagonist in male dogs Reviewed International journal

    Ken Ichi Noritake, Junko Suzuki, Toshiki Matsuoka, Toshihiko Makino, Hitoshi Ohnishi, Kazuhiro Shimomura, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Atsushi Sanbuissho

    Reproductive Toxicology   Vol. 31 ( 4 ) page: 440 - 446   2011.5

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    Mechanism mediating the testicular toxicity induced by CS-003, a triple neurokinin receptor antagonist, was investigated in male dogs. Daily CS-003 administrations showed testicular toxicity, such as a decrease in the sperm number, motility and prostate weight; and an increase in sperm abnormality, accompanying histopathological changes in the testis, epididymis and prostate. A single CS-003 administration suppressed plasma testosterone and LH levels in intact and castrated males. The suppressed LH release was restored by GnRH agonist injection, suggesting that pituitary sensitivity to GnRH is not impaired by CS-003. Treatment with SB223412, a neurokinin 3 receptor antagonist, caused a similar effect to CS-003, such as toxicity in the testis, prostate and epididymis and decreased plasma level of LH and testosterone. In conclusion, CS-003-induced testicular toxicity is caused by the inhibition of neurokinin B/neurokinin 3 receptor signaling probably at the hypothalamic level in male dogs. © 2010 Elsevier Inc.

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  97. Involvement of brain ketone bodies and the noradrenergic pathway in diabetic hyperphagia in rats Reviewed

    Kinuyo Iwata, Mika Kinoshita, Shunji Yamada, Takuya Imamura, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Physiological Sciences   Vol. 61 ( 2 ) page: 103 - 113   2011.3

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    Uncontrolled type 1 diabetes leads to hyperphagia and severe ketosis. This study was conducted to test the hypothesis that ketone bodies act on the hindbrain as a starvation signal to induce diabetic hyperphagia. Injection of an inhibitor of monocarboxylate transporter 1, a ketone body transporter, into the fourth ventricle normalized the increase in food intake in streptozotocin (STZ)-induced diabetic rats. Blockade of catecholamine synthesis in the hypothalamic paraventricular nucleus (PVN) also restored food intake to normal levels in diabetic animals. On the other hand, hindbrain injection of the ketone body induced feeding, hyperglycemia, and fatty acid mobilization via increased sympathetic activity and also norepinephrine release in the PVN. This result provides evidence that hyperphagia in STZ-induced type 1 diabetes is signaled by a ketone body sensed in the hindbrain, and mediated by noradrenergic inputs to the PVN.© The Physiological Society of Japan and Springer 2011.

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  98. Activation of neuropeptide FF receptors by kisspeptin receptor ligands Reviewed International journal

    Shinya Oishi, Ryosuke Misu, Kenji Tomita, Shohei Setsuda, Ryo Masuda, Hiroaki Ohno, Yousuke Naniwa, Nahoko Ieda, Naoko Inoue, Satoshi Ohkura, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Akira Hirasawa, Gozoh Tsujimoto, Nobutaka Fujii

    ACS Medicinal Chemistry Letters   Vol. 2 ( 1 ) page: 53 - 57   2011.1

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    Kisspeptin is a member of the RFamide neuropeptide family that is implicated in gonadotropin secretion. Because kisspeptin-GPR54 signaling is implicated in the neuroendocrine regulation of reproduction, GPR54 ligands represent promising therapeutic agents against endocrine secretion disorders. In the present study, the selectivity profiles of GPR54 agonist peptides were investigated for several GPCRs, including RFamide receptors. Kisspeptin-10 exhibited potent binding and activation of neuropeptide FF receptors (NPFFR1 and NPFFR2). In contrast, short peptide agonists bound with much lower affinity to NPFFRs while showing relatively high selectivity toward GPR54. The possible localization of secondary kisspeptin targets was also demonstrated by variation in the levels of GnRH release from the median eminence and the type of GPR54 agonists used. Negligible affinity of the reported NPFFR ligands to GPR54 was observed and indicates the unidirectional cross-reactivity between both ligands. © 2010 American Chemical Society.

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  99. Morphological evidence for direct interaction between kisspeptin and gonadotropin-releasing hormone neurons at the median eminence of the male goat: An immunoelectron microscopic study Reviewed International journal

    Shuichi Matsuyama, Satoshi Ohkura, Kazutaka Mogi, Yoshihiro Wakabayashi, Yuji Mori, Hiroko Tsukamura, Kei Ichiro Maeda, Masumi Ichikawa, Hiroaki Okamura

    Neuroendocrinology   Vol. 94 ( 4 ) page: 323 - 332   2011

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    Kisspeptin has been thought to play pivotal roles in the control of both pulse and surge modes of gonadotropin-releasing hormone (GnRH) secretion. To clarify loci of kisspeptin action on GnRH neurons, the present study examined the morphology of the kisspeptin system and the associations between kisspeptin and GnRH systems in gonadally intact and castrated male goats. Kisspeptin-immunoreactive (ir) and Kiss1-positive neurons were found in the medial preoptic area of intact but not castrated goats. Kisspeptin-ir cell bodies and fibers in the arcuate nucleus (ARC) and median eminence (ME) were fewer in intact male goats compared with castrated animals. Apposition of kisspeptin-ir fibers on GnRH-ir cell bodies was very rare in both intact and castrated goats, whereas the intimate association of kisspeptin-ir fibers with GnRH-ir nerve terminals was observed in the ME of castrated animals. Neurokinin B immunoreactivity colocalized not only in kisspeptin-ir cell bodies in the ARC but also in kisspeptin-ir fibers in the ME, suggesting that a majority of kisspeptin-ir fibers projecting to the ME originates from the ARC. A dual immunoelectron microscopic examination revealed that nerve terminals containing kisspeptin-ir vesicles made direct contact with GnRH-ir nerve terminals at the ME of castrated goats. There was no evidence for the existence of the typical synaptic structure between kisspeptin-and GnRH-ir fibers. The present results suggest that the ARC kisspeptin neurons act on GnRH neurons at the ME to control (possibly the pulse mode of) GnRH secretion in males. © 2011 S. Karger AG, Basel.

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  100. GnRH Pulse Generation and Its Application to the Manipulation of Follicular Development and Ovulation Reviewed

    Hiroko Tsukamura, Kei-ichiro Maeda

    THAI JOURNAL OF VETERINARY MEDICINE   Vol. 41   page: 69 - 72   2011

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    The hypothalamo-pituitary-gonadal axis, plays a key role in the control of gonadal functions, such as follicular development, ovulation, spermatogenesis and steroidogenesis in mammals. Pulsatile gonadotropirt-releasing hormone (GnRH) release drives tonic secretion of gonadotropin which mainly regulates folliculogenesis and steroidogenesis. On the other hand, the surge mode of GnRH generates the preovulatory LH surge which triggers ovulation. Accumulating evidence suggest that the kisspeptin neuron in the hypothalamus acts as a critical player in the mechanism governing pulsatile and surge modes of GnRH secretion. This paper focuses on the role of kisspeptin neurons in controlling mammalian reproduction in order to apply the mechanism for the manipulation of animal reproduction.

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  101. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus International journal

    Kei Ichiro Maeda, Satoshi Ohkura, Yoshihisa Uenoyama, Yoshihiro Wakabayashi, Yoshitaka Oka, Hiroko Tsukamura, Hiroaki Okamura

    Brain Research   Vol. 1364   page: 103 - 115   2010.12

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    Gonadotropin-releasing hormone (GnRH) secretion has two modes of release in mammalian species; the surge mode and the pulse mode. The surge mode, which is required for the induction of the preovulatory gonadotropin discharge in most species, is induced by the positive feedback of estrogen secreted by the mature ovarian follicle. The pulse mode of GnRH secretion stimulates tonic luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion which drives folliculogenesis, spermatogenesis and steroidogenesis and is negatively fine-tuned by estrogen or androgen. The GnRH pulse-generating mechanism is sensitive to environmental cues, such as photoperiod, nutrition and stress surge-generating mechanism is relatively emancipated from these environmental cues. The present article first provides a brief historical background to the work that led to the concept of the GnRH pulse generator: a hypothalamic network that is central to our understanding of the regulation of reproduction. We then discuss possible neurobiological mechanisms underlying GnRH pulse generation, and conclude by proposing that kisspeptin neurons in the arcuate nucleus are key players in this regard. © 2010 Elsevier B.V.

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  102. Potential of promoter-associated noncoding RNAs for epigenetic setting during differentiation Reviewed

    Naoki Yamamoto, Nobuhiko Hamazaki, Masahiro Uesaka, Hiroko Shimokawa, Hiroko Tsukamura, Kei-ichiro Maeda, Yuji Mori, Takuya Imamura

    DIFFERENTIATION   Vol. 80   page: S29 - S29   2010.11

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  103. Acute trapping of peripubertal kisspeptin or leptin with antibodies to determine factors triggering the onset of puberty in female rats Reviewed

    Yoshihisa Uenoyama, Kenji Takase, Junya Hirata, Akira Tanaka, Hiroko Tsukamura, Kei-ichiro Maeda

    ENDOCRINE JOURNAL   Vol. 57   page: S534 - S534   2010.3

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  104. Effect of neonatal estrogen on brain kisspeptin expression in adult mice: possible role of estrogen receptor alpha Reviewed

    Kae Yoshida, Tamami Homma, Yoko Inamoto, Junko Tomikawa, Yoshihisa Uenoyama, Kei-ichiro Maeda, Hiroko Tsukamura

    ENDOCRINE JOURNAL   Vol. 57   page: S533 - S534   2010.3

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  105. Kisspeptin neurons responsible for animal reproduction: Surge vs. pulse modes of GnRH/LH secretion and its sex difference Reviewed

    Hiroko Tsukamura, Kei-ichiro Maeda

    ENDOCRINE JOURNAL   Vol. 57   page: S251 - S251   2010.3

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  106. Induction of ovulation by kisspeptin and its agonists in the musk shrew (Suncus murinus), a reflex ovulator Reviewed

    Inoue Naoko, Sasaki Yuki, Oishi Shinya, Fujii Nobutaka, Uenoyama Yoshihisa, Yamamoto Naoyuki, Tsukamura Hiroko, Maeda Kei-ichiro

    ENDOCRINE JOURNAL   Vol. 57   page: S517 - S517   2010.3

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  107. Gonadotropin-releasing hormone pulse generator activity from the arcuate nucleus kisspeptin neurons in the goat hypothalamus Reviewed

    Ohkura Satoshi, Wakabayashi Yoshihiro, Uenoyama Yoshihisa, Steiner Robert A., Tsukamura Hiroko, Maeda Kei-ichiro, Okamura Hiroaki

    ENDOCRINE JOURNAL   Vol. 57   page: S516 - S516   2010.3

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  108. Molecular characterization of Kiss 1 gene in the pig Reviewed

    Junko Tomikawa, Tamami Homma, Shigeyuki Tajima, Takako Shibata, Yoko Inamoto, Satoshi Ohkura, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-ichiro Maeda

    ENDOCRINE JOURNAL   Vol. 57   page: S516 - S516   2010.3

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  109. The significance of the depletion of neonatal testicular androgens to rescue anteroventral periventricular Kiss1 neurons and GnRH/LH surge in male rats Reviewed

    Homma Tamami, Yamada Shunji, Iwata Kinuyo, Tomikawa Junko, Uenoyama Yoshihisa, Maeda Kei-ichiro, Okamura Hiroaki, Tsukamura Hiroko

    ENDOCRINE JOURNAL   Vol. 57   page: S534 - S534   2010.3

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  110. Neurokinin B and dynorphin A in kisspeptin neurons of the arcuate nucleus participate in generation of periodic oscillation of neural activity driving pulsatile gonadotropin-releasing hormone secretion in the goat Reviewed International journal

    Yoshihiro Wakabayashi, Tomoaki Nakada, Ken Murata, Satoshi Ohkura, Kazutaka Mogi, Victor M. Navarro, Donald K. Clifton, Yuji Mori, Hiroko Tsukamura, Kei Ichiro Maeda, Robert A. Steiner, Hiroaki Okamura

    Journal of Neuroscience   Vol. 30 ( 8 ) page: 3124 - 3132   2010.2

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    Gonadotropin-releasing hormone (GnRH) neurons in the basal forebrain are the final common pathway through which the brain regulates reproduction. GnRH secretion occurs in a pulsatile manner, and indirect evidence suggests the kisspeptin neurons in the arcuate nucleus (ARC) serve as the central pacemaker that drives pulsatile GnRH secretion. The purpose of this study was to investigate the possible coexpression of kisspeptin, neurokinin B (NKB), and dynorphin A (Dyn) in neurons of the ARC of the goat and evaluate their potential roles in generatingGnRHpulses. Using double and triple labeling, we confirmed that all three neuropeptides are coexpressed in the same population of neurons. Using electrophysiological techniques to record multiple-unit activity (MUA) in the medial basal hypothalamus, we found that bursts of MUA occurred at regular intervals in ovariectomized animals and that these repetitive bursts (volleys) were invariably associated with discrete pulses of luteinizing hormone (LH) (and by inference GnRH). Moreover, the frequency of MUA volleys was reduced by gonadal steroids, suggesting that the volleys reflect the rhythmic discharge of steroid-sensitive neurons that regulate GnRH secretion. Finally, we observed that central administration of Dyn-inhibit MUA volleys and pulsatile LH secretion, whereas NKB induced MUA volleys. These observations are consistent with the hypothesis that kisspeptin neurons in the ARC drive pulsatile GnRH and LH secretion, and suggest that NKB and Dyn expressed in those neurons are involved in the process of generating the rhythmic discharge of kisspeptin. Copyright © 2010 the authors.

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  111. Molecular characterization and estrogen regulation of hypothalamic KISS1 gene in the pig. Reviewed International journal

    Junko Tomikawa, Tamami Homma, Shigeyuki Tajima, Takako Shibata, Yoko Inamoto, Kenji Takase, Naoko Inoue, Satoshi Ohkura, Yoshihisa Uenoyama, Kei ichiro Maeda, Hiroko Tsukamura

    Biology of reproduction   Vol. 82 ( 2 ) page: 313 - 319   2010.2

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    Kisspeptin-GPR54 signaling plays an essential role in normal reproduction in mammals via stimulation of gonadotropin secretion. Here, we cloned the porcine KISS1 cDNA from the hypothalamic tissue and investigated the effect of estrogen on the distribution and numbers of KISS1 mRNA-expressing cells in the porcine hypothalamus. The full length of the cDNA was 857 bp encoding the kisspeptin of 54 amino acids, with the C-terminal active motif designated kisspeptin-10 being identical to that of mouse, rat, cattle, and sheep. In situ hybridization analysis revealed that KISS1-positive cell populations were mainly distributed in the hypothalamic periventricular nucleus (PeN) and arcuate nucleus (ARC). KISS1 expression in the PeN of ovariectomized (OVX) pigs was significantly upregulated by estradiol benzoate (EB) treatment. On the other hand, KISS1-expressing cells were abundantly distributed throughout the ARC in both OVX and OVX with EB animals. The number of KISS1-expressing neurons was significantly lowered by EB treatment only in the most caudal part of the ARC, but other ARC populations were not affected. The present study thus suggests that the PeN kisspeptin neurons could be responsible for the estrogen positive feedback regulation to induce gonadotropin-releasing hormone/luteinizing hormone (GnRH/LH) surge in the pig. In addition, the caudal ARC kisspeptin neurons could be involved in the estrogen negative feedback regulation of GnRH/LH release. This is the first report of identification of porcine KISS1 gene and of estrogen regulation of KISS1 expression in the porcine brain, which may be helpful for better understanding of the role of kisspeptin in reproduction of the pig.

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  112. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus. Reviewed

    Maeda, K.-I., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H., and Okamura, H.

    Brain Research     page: in press   2010

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  113. Kiss1 cDNA Cloning and Induction of Ovulation by Peripheral Administration of Various Kisspeptins in the Musk Shrew (Suncus murinus), a Reflex Ovulator.

    Inoue Naoko, Tomikawa Junko, Sasaki Yuki, Uchida Akira, Oishi Shinya, Fujii Nobutaka, Uenoyama Yoshihisa, Yamamoto Naoyuki, Maeda Keiichiro, Tsukamura Hiroko

    BIOLOGY OF REPRODUCTION     page: 172 - 172   2010

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  114. Kisspeptin Neurons in the Hypothalamic Arcuate Nucleus Are Potent Stimulators of GnRH/LH Secretion in Holstein Steers. Reviewed

    Ohkura Satoshi, Takase Kenji, Wakabayashi Yoshihiro, Yayou Ken-ichi, Uenoyama Yoshihisa, Tsukamura Hiroko, Maeda Kei-ichiro, Okamura Hiroaki

    BIOLOGY OF REPRODUCTION     page: 174 - 174   2010

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  115. Molecular and Physiological Characterization of the Porcine Kisspeptin. Reviewed

    Junko Tomikawa, Tamami Homma, Satoshi Ohkura, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei-ichiro Maeda

    BIOLOGY OF REPRODUCTION     page: 175 - 175   2010

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  116. The Role of Neural Inputs from the Posterior Arcuate Nucleus in Pulsatile Luteinizing Hormone Release in Ovariectomized Rats. Reviewed

    Yoshihisa Uenoyama, Saya Watanabe, Kinuyo Iwata, Satoshi Ohkura, Kei-ichiro Maeda, Hiroko Tsukamura

    BIOLOGY OF REPRODUCTION     page: 174 - 174   2010

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  117. Sexual differentiation of kisspeptin neurons responsible for sex difference in gonadotropin release in rats Reviewed International journal

    Hiroko Tsukamura, Tamami Homma, Junko Tomikawa, Yoshihisa Uenoyama, Kei Ichiro Maeda

    Annals of the New York Academy of Sciences   Vol. 1200   page: 95 - 103   2010

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    The brain mechanism regulating GnRH/luteinizing hormone (LH) release is sexually differentiated in rodents. Estrogen induces a GnRH/LH surge in females but not in males. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) have been reported to be sexually dimorphic and suggested to be involved in the GnRH/LH surge generation. Neonatal testicular androgen may cause the reduction of AVPV kisspeptin expression and a lack of LH surge in male rats. Thus, it is plausible that perinatal testicular androgen causes defeminization of the AVPV kisspeptin system, resulting in the loss of the surge system in male rats. © 2010 New York Academy of Sciences.

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  118. Significance of neonatal testicular sex steroids to defeminize anteroventral periventricular kisspeptin neurons and the GnRH/LH surge system in male rats Reviewed International journal

    Tamami Homma, Mototsugu Sakakibara, Shunji Yamada, Mika Kinoshita, Kinuyo Iwata, Junko Tomikawa, Tetsuhiro Kanazawa, Hisanori Matsui, Yoshihiro Takatsu, Tetsuya Ohtaki, Hirokazu Matsumoto, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Biology of Reproduction   Vol. 81 ( 6 ) page: 1216 - 1225   2009.12

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    The brain mechanism regulating gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) release is sexually differentiated in rodents. Kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) have been suggested to be sexually dimorphic and involved in the GnRH/LH surge generation. The present study aimed to determine the significance of neonatal testicular androgen to defeminize AVPV kisspeptin expression and the GnRH/LH surge-generating system. To this end, we tested whether neonatal castration feminizes AVPV kisspeptin neurons and the LH surge-generating system in male rats and whether neonatal estradiol benzoate (EB) treatment suppresses the kisspeptin expression and the LH surge in female rats. Immunohistochemistry, in situ hybridization, and quantitative real-time RT-PCR were performed to investigate kisspeptin and Kiss1 mRNA expressions. Male rats were castrated immediately after birth, and females were treated with EB on postnatal Day 5. Neonatal castration caused an increase in AVPV kisspeptin expression at peptide and mRNA levels in the genetically male rats, and the animals showed surge-like LH release in the presence of the preovulatory level of estradiol (E2) at adulthood. On the other hand, neonatal EB treatment decreased the number of AVPV kisspeptin neurons and caused an absence of E2-induced LH surge in female rats. Semiquantitative RT-PCR analysis showed that neonatal steroidal manipulation affects Kiss1 expression but does not significantly affect gene expressions of neuropeptides (neurotensin and galanin) and enzymes or transporter for neurotransmitters (gamma-amino-butyric acid, glutamate, and dopamine) in the AVPV, suggesting that the manipulation specifically affects Kiss1 expressions. Taken together, our present results provide physiological evidence that neonatal testicular androgen causes the reduction of AVPV kisspeptin expression and failure of LH surge in genetically male rats. Thus, it is plausible that perinatal testicular androgen causes defeminization of the AVPV kisspeptin system, resulting in the loss of the surge system in male rats. © 2009 by the Society for the Study of Reproduction, Inc.

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  119. Gonadotrophin-releasing hormone pulse generator activity in the hypothalamus of the goat Reviewed

    S. Ohkura, K. Takase, S. Matsuyama, K. Mogi, T. Ichimaru, Y. Wakabayashi, Y. Uenoyama, Y. Mori, R. A. Steiner, H. Tsukamura, K. I. Maeda, H. Okamura

    Journal of Neuroendocrinology   Vol. 21 ( 10 ) page: 813 - 821   2009.10

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    Pulsatile release of gonadotrophin-releasing hormone (GnRH) is indispensable to maintain normal gonadotrophin secretion. The pulsatile secretion of GnRH is associated with synchronised electrical activity in the mediobasal hypothalamus (i.e. multiple unit activity; MUA), which is considered to reflect the rhythmic oscillations in the activity of the neuronal network that drives pulsatile GnRH secretion. However, the cellular source of this ultradian rhythm in GnRH activity is unknown. Direct input from kisspeptin neurones in the arcuate nucleus (ARC) to GnRH cell bodies in the medial preoptic area or their terminals in the median eminence could be the intrinsic source for driving the GnRH pulse generator. To determine whether kisspeptin signalling could be responsible for producing pulsatile GnRH secretion, we studied goats, measured plasma levels of luteinising hormone (LH) and recorded MUA in the posterior ARC, where the majority of kisspeptin neuronal cell bodies are located. Rhythmic volleys of MUA were found to be accompanied by LH pulses with regular intervals in the ARC, where kisspeptin neuronal cell bodies were found. Exogenous administration of kisspeptin stimulated a sustained increase in LH secretion, without influencing MUA, suggesting that the GnRH pulse generator, as reflected by MUA, originated from outside of the network of GnRH neurones, and could plausibly reflect the pacemaker activity of kisspeptin neurones, whose projections reach the median eminence where GnRH fibres project. These observations suggest that the kisspeptin neurones in the ARC may be the intrinsic source of the GnRH pulse generator. © 2009 The Authors. Journal Compilation © 2009 Blackwell Publishing Ltd.

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  120. Potencies of centrally-or peripherally-injected full-length kisspeptin or its C-terminal decapeptide on LH release in intact male rats Reviewed

    Vutha Pheng, Yoshihisa Uenoyama, Tamami Homma, Yoko Inamoto, Kenji Takase, Kumiko Yoshizawa-Kumagaye, Shuji Isaka, Takushi X. Watanabe, Satoshi Ohkura, Junko Tomikawa, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 55 ( 4 ) page: 378 - 382   2009.8

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    The aim of the present study was to compare the effects of full-length rat kisspeptin (rKp-52) with C-terminal decapeptide (Kp-10) of rat or human kisspeptin on LH release in intact male rats. Plasma LH profiles were determined by frequent blood sampling at 6-min intervals for 3 h after central or peripheral injection of kisspeptins. Intracerebroventricular (icv) injection of rKp-52 (0.1 nmol) induced a gradual increase in the plasma LH level, which remained high for the rest of the sampling period. On the other hand, icv injection of rKp-10 did not increase the plasma LH level at the same dose (0.1 nmol). A 10-times higher dose (1 nmol) of rKp-10 and hKp-10 increased the plasma LH level, but the increase was lower than that of rKp-52 icv injection. Intravenous (iv) injection of kisspeptins also stimulated LH release at 10 or 100 nmol/kg. In rKp-52 (10 nmol/kg)-treated animals, the plasma LH level reached a peak within 30 min and remained high until 60 min postinjection. The rKp-10- and hKp-10-injected animals showed a more rapid decline in plasma LH level after the peak found at around 30 min after the injections at both middle (10 nmol/kg) and high (100 nmol/kg) doses. The present study indicates that full-length kisspeptin is more effective in stimulating LH release compared with Kp-10 in male rats. The difference in LH-releasing activity may be the result of a difference in degradation of the peptides, but it is still worth determining whether an active domain other than the C-terminal decapeptide is present in full-length kisspeptin.

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  121. Food deprivation induces monocarboxylate transporter 2 expression in the brainstem of female rat Reviewed

    Shuichi Matsuyama, Satoshi Ohkura, Kinuyo Iwata, Yoshihisa Uenoyama, Hiroko Tsukamura, Kei Ichiro Maeda, Koji Kimura

    Journal of Reproduction and Development   Vol. 55 ( 3 ) page: 256 - 61   2009.6

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    Ketone bodies are considered to act as a signal to suppress gonadotropin release during negative energy balance. The present study examined the effect of 48-h fasting on the mRNA expressions of monocarboxylate transporter 1 (MCT1) and MCT2, which are involved in ketone body transport, in several brain regions. Quantitative real-time RT-PCR analysis showed that the MCT2 mRNA levels were significantly increased by 48-h fasting in the area postrema-solitary tract nucleus (AP-NTS) region but not the arcuate nucleus-ventromedial hypothalamic nucleus (ARC-VMH) and central gray-supragenual nucleus around the 4th ventricle (CG-SGe) regions. Fasting did not significantly affect MCT1 mRNA expression in any of the brain areas examined. Luteinizing hormone (LH) pulse frequency significantly decreased and plasma concentrations of β-hydroxybutyric acid, a ketone body, significantly increased after 48-h fasting. The present results suggest that increased uptake of ketone bodies via MCT2 in the AP-NTS region is likely involved in the mechanism of fasting-induced suppression of LH secretion in rats.

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  122. Neural Pathway of Estrogen Receptor alpha Expression During Stress-induced Suppression of Luteinizing Hormone Secretion Reviewed

    Estacio Maria Amelita C., Tsukamura Hiroko, de Luna Maria Catalina T., Maeda Kei-Ichiro

    PHILIPPINE JOURNAL OF VETERINARY MEDICINE   Vol. 46 ( 1 ) page: 61 - 72   2009.6

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  123. Possible role of oestrogen in pubertal increase of Kiss1/kisspeptin expression in discrete hypothalamic areas of female rats Reviewed

    K. Takase, Y. Uenoyama, N. Inoue, H. Matsui, S. Yamada, M. Shimizu, T. Homma, J. Tomikawa, S. Kanda, H. Matsumoto, Y. Oka, H. Tsukamura, Kei Ichiro Maeda

    Journal of Neuroendocrinology   Vol. 21 ( 6 ) page: 527 - 537   2009.6

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    Kisspeptin, a peptide encoded by the Kiss1 gene, has been considered as a potential candidate for a factor triggering the onset of puberty, and its expression in the hypothalamus was found to increase during peripubertal period in rodent models. The present study aimed to clarify the oestrogenic regulation of peripubertal changes in Kiss1 mRNA expression in the anteroventral periventricular nucleus (AVPV) and hypothalamic arcuate nucleus (ARC), and to determine which population of kisspeptin neurones shows a change in kisspeptin expression parallel to that in luteinising hormone (LH) pulses at the peripubertal period. Quantitative reverse transcriptase-polymerase chain reaction and immunohistochemistry revealed an apparent increase in the ARC Kiss1 mRNA expression and kisspeptin immunoreactivity around the time of vaginal opening in intact female rats. The AVPV Kiss1 mRNA levels also increased at day 26, but decreased at day 31, and then increased at day 36/41. In ovariectomised (OVX) rats, ARC Kiss1 mRNA expression did not show peripubertal changes and was kept at a high level throughout peripubertal periods. Apparent LH pulses were found in these prepubertal OVX rats. Oestradiol replacement suppressed ARC Kiss1 mRNA expression in OVX prepubertal rats, but not in adults. Similarly, LH pulses were suppressed by oestradiol in the prepubertal period (days 21 and 26), but regular pulses were found in adulthood. The present study suggests that a pubertal increase of Kiss1/kisspeptin expression both in the ARC and AVPV is involved in the onset of puberty. These results also suggest that both LH pulses and ARC Kiss1 expression are more negatively regulated by oestrogen in prepubertal female rats compared to adult rats. © 2009 The Authors. Journal compilation © 2009 Blackwell Publishing.

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  124. Kisspeptin/metastin: A key molecule controlling two modes of gonadotrophin-releasing hormone/luteinising hormone release in female rats Reviewed

    Y. Uenoyama, H. Tsukamura, Kei Ichiro Maeda

    Journal of Neuroendocrinology   Vol. 21 ( 4 ) page: 299 - 304   2009.4

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    Kisspeptin (also known as metastin), a hypothalamic peptide, has attracted attention as a key molecule in the release of gonadotrophin-releasing hormone (GnRH) in various mammalian species, such as rodents, sheep and primates. Two populations of kisspeptin neurones in the brain may control two modes of GnRH release to time the onset of puberty and regulate oestrous cyclicity in rats and mice. One population of kisspeptin neurones, located in the anteroventral periventricular nucleus, appears to be responsible for the induction of the GnRH surge that leads to the luteinising hormone surge and ovulation. The other, located in the hypothalamic arcuate nucleus, appears to be involved in generating GnRH pulses, resulting in luteinising hormone pulses followed by follicular development and steroidogenesis in the ovary. The present review focuses on the physiological role of the two populations of kisspeptin neurones in controlling gonadal functions by generating the two modes of GnRH release in a female rat model. © 2009 The Authors. Journal compilation © 2009 Blackwell Publishing.

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  125. Physiological role of metastin/kisspeptin in regulating gonadotropin-releasing hormone (GnRH) secretion in female rats Reviewed International journal

    Satoshi Ohkura, Yoshihisa Uenoyama, Shunji Yamada, Tamami Homma, Kenji Takase, Naoko Inoue, Kei ichiro Maeda, Hiroko Tsukamura

    Peptides   Vol. 30 ( 1 ) page: 49 - 56   2009.1

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    Various studies have attempted to unravel the physiological role of metastin/kisspeptin in the control of gonadotropin-releasing hormone (GnRH) release. A number of evidences suggested that the population of metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) is involved in generating a GnRH surge to induce ovulation in rodents, and thus the target of estrogen positive feedback. Females have an obvious metastin/kisspeptin neuronal population in the AVPV, but males have only a few cell bodies in the nucleus, suggesting that the absence of the surge-generating mechanism or positive feedback action in males is due to the limited AVPV metastin/kisspeptin neuronal population. On the other hand, the arcuate nucleus (ARC) metastin/kisspeptin neuronal population is considered to be involved in the regulation of tonic GnRH release. The ARC metastin/kisspeptin neurons show no sex difference in their expression, which is suppressed by gonadal steroids in both sexes. Thus, the ARC population of metastin/kisspeptin neurons is a target of estrogen negative feedback action on tonic GnRH release. The lactating rat model provided further evidence indicating that ARC metastin/kisspeptin neurons are involved in GnRH pulse generation, because pulsatile release of luteinizing hormone (LH) is profoundly suppressed by suckling stimulus and the LH pulse suppression is well associated with the suppression of ARC metastin/kisspeptin and KiSS-1 gene expression in lactating rats. © 2008 Elsevier Inc. All rights reserved.

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  126. CENTRAL METASTIN/KISSPEPTIN IN THE REGULATION OF LUTEINIZING HORMONE SECRETION Reviewed

    Hiroko Tsukamura, Kei-ichiro Maeda

    JOURNAL OF PHYSIOLOGICAL SCIENCES   Vol. 59   page: 29 - 29   2009

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  127. Localization of Kisspeptin and Gonadotropin-Releasing Hormone (GnRH) in Developing Ovarian Follicles of Pigs and Goals. Reviewed

    Inoue Naoko, Hirano Takayuki, Uenoyama Yoshihisa, Tsukamura Hiroko, Okamota Hiroaki, Maeda Kei-ichiro

    BIOLOGY OF REPRODUCTION     page: 174 - 174   2009

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  128. Central lipoprivation-induced suppression of luteinizing hormone pulses is mediated by paraventricular catecholaminergic inputs in female rats

    Sajapitak Somchai, Iwata Kinuyo, Shahab Mohammad, Uenoyama Yoshihisa, Yamada Shunji, Kinoshita Mika, Bari Farida Y., I'Anson Helen, Tsukamura Hiroko, Maeda Kei-ichiro

    ENDOCRINOLOGY   Vol. 149 ( 6 ) page: 3016 - 3024   2008.6

  129. Paraventricular α1- and α2-adrenergic receptors mediate hindbrain lipoprivation-induced suppression of luteinizing hormone pulses in female rats Reviewed

    Somchai Sajapitak, Yoshihisa Uenoyama, Shunji Yamada, Mika Kinoshita, Kinuyo Iwata, Farida Yeasmin Bari, Helen I'Anson, Hiroko Tsukamula, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 54 ( 3 ) page: 198 - 202   2008.6

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    Acute central lipoprivation suppresses pulsatile luteinizing hormone (LH) release and increases blood glucose levels through noradrenergic input to the hypothalamic paraventricular nucleus (PVN) in female rats. The present study was conducted to identify adrenergic receptor subtypes involved in central lipoprivation-induced suppression of pulsatile LH secretion and increases in plasma glucose levels in female rats. Acute hindbrain lipoprivation was produced by injection into the fourth cerebroventricle (4V) of 2-mercaptoacetate (MA), an inhibitor of fatty acid oxidation, in estradiol-implanted ovariectomized rats. Two min before MA injection, α1-, α2- or β-adrenergic receptor antagonist was injected into the PVN. Injection of MA into the 4V suppresses pulsatile LH release in PVN vehicle-treated rats, whereas pretreatment of animals with injection of α1- or α2-adrenergic antagonist into the PVN blocked the effect of the 4V MA injection on LH pulses. β-Adrenergic antagonist did not affect MA-induced suppression of LH pulses. The counter-regulatory increase in plasma glucose levels after 4V MA injection was also partially blocked by pretreatment with α1- and α2-adrenergic receptor antagonists. These results suggest that α1- and α2-adrenergic receptors in the PVN mediate hindbrain lipoprivation-induced suppression of LH release and counterregulatory increases in plasma glucose levels in female rats.

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  130. Identification of KiSS-1 product kisspeptin and steroid-sensitive sexually dimorphic kisspeptin neurons in Medaka (Oryzias latipes) Reviewed International journal

    Shinji Kanda, Yasuhisa Akazome, Takuya Matsunaga, Naoyuki Yamamoto, Shunji Yamada, Hiroko Tsukamura, Kei Ichiro Maeda, Yoshitaka Oka

    Endocrinology   Vol. 149 ( 5 ) page: 2467 - 2476   2008.5

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    Recently, a novel physiologically active peptide, kisspeptin (metastin), has been reported to facilitate sexual maturation and ovulation by directly stimulating GnRH neurons in several mammalian species. Despite its importance in the neuroendocrine regulation of reproduction, kisspeptin neurons have only been studied in mammals, and there has been no report on the kisspeptin or kisspeptin neuronal systems in nonmammalian vertebrates. We used medaka for the initial identification of the KiSS-1 gene and the anatomical distribution of KiSS-1 mRNA expressing neurons (KiSS-1 neurons) in the brain of nonmammalian species. In situ hybridization for the medaka KiSS-1 gene cloned here proved that two kisspeptin neuronal populations are localized in the hypothalamic nuclei, the nucleus posterioris periventricularis and the nucleus ventral tuberis (NVT). Furthermore, NVT KiSS-1 neurons were sexually dimorphic in number (male neurons≫ female neurons) under the breeding conditions.Wealso found that the number of KiSS-1 neurons in the NVT but not that in the nucleus posterioris periventricularis was positively regulated by ovarian estrogens. The fact that there were clear differences in the number of NVT KiSS-1 neurons between the fish under the breeding and nonbreeding conditions strongly suggests that the steroid-sensitive changes in the KiSS-1 mRNA expression in the NVT occur physiologically, according to the changes in the reproductive state. From the present results, we conclude that the medaka KiSS-1 neuronal system is involved in the central regulation of reproductive functions, and, given many experimental advantages, the medaka brain may serve as a good model system to study its physiology. Copyright © 2008 by The Endocrine Society.

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  131. Oestrogen-dependent stimulation of luteinising hormone release by galanin-like peptide in female rats Reviewed

    Y. Uenoyama, H. Tsukamura, M. Kinoshita, S. Yamada, K. Iwata, V. Pheng, S. Sajapitak, M. Sakakibara, T. Ohtaki, H. Matsumoto, Kei Ichiro Maeda

    Journal of Neuroendocrinology   Vol. 20 ( 5 ) page: 626 - 631   2008.5

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    Galanin-like peptide (GALP), a ligand for three types of galanin receptor, is reported to have a role in regulating luteinising hormone (LH) release in male rodents and primates, but its role in LH release in female rodents remains controversial. The present study was conducted to test whether GALP has a stimulatory role in regulating LH secretion in female rats. The effect of i.c.v. infusion of GALP (5nmol) on pulsatile LH release was investigated in Wistar-Imamichi strain female rats, or lean and obese Zucker rats. In oestradiol-17β (oestradiol)-primed ovariectomised (OVX) Wistar-Imamichi female rats, i.c.v. infusion of GALP caused a gradual increase in LH release for the first 1.5h after the infusion followed by an increased LH pulse frequency during the next 1.5h, resulting in a significant increase in the mean LH concentrations and baseline levels of LH pulses throughout the sampling period and in the frequency of LH pulses at the last half of the period compared to vehicle-treated controls. The stimulatory effect of GALP was oestrogen-dependent because the same GALP treatment did not affect LH release in OVX rats in the absence of oestradiol. In lean Zucker rats, LH pulses were found in oestradiol-primed OVX individuals and central GALP infusion increased mean LH concentrations in the last half of the period. By contrast, few LH pulses were found in oestradiol-primed OVX obese Zucker rats reportedly with lower hypothalamic GALP expression. Central GALP infusion caused an apparent but transient increase in LH release, resulting in the significant increase in all pulse parameters of LH pulses compared to vehicle-treated controls in the first half of the sampling period. These results suggest that hypothalamic GALP is likely involved in stimulating GnRH/LH release, and that the stimulatory effect of GALP on LH release is oestrogen-dependent in female rats. © 2008 The Authors. Journal Compilation © 2008 Blackwell Publishing.

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  132. The role of arcuate metastin neurons in regulation of pulsatile GnRH/LH secretion in the female rat

    Inamoto Yoko, Maeda Maki, Homma Tarnarni, Yamada Shunji, Uenoyama Yoshihisa, Ohkura Satoshi, Maeda Kei-ichiro, Tsukamura Hiroko

    JOURNAL OF REPRODUCTION AND DEVELOPMENT   Vol. 54 ( 1 ) page: A5 - A5   2008.2

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  133. Identification of KiSS-1 product kisspeptin and steroid-sensitive sexually dimorphic kisspeptin neurons in medaka (oryzias latipes). Reviewed

    Kanda, S., Akazome, Y., Matsunaga, T., Yamamoto, N., Yamada, S., Tsukamura, H., Maeda, K.-I. and Oka, Y.

    Endocrinology   ( 149 ) page: 2467 - 2476   2008

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  134. Brain ketone body sensing involved in the suppression of pulsatile luteinizing hormone release in female rats

    Iwata Kinuyo, Kinoshita Mika, Susaki Naoki, Homma Tamami, Tsukamura Hiroko, Maeda Kei-ichiro

    BIOLOGY OF REPRODUCTION     page: 308 - 309   2008

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  135. The absence in the neonatal androgen is essential for the presence of anteroventral periventricular metastin neurons and GnRH/LH surge system in the adult

    Homma Tamami, Uenoyama Yoshihisa, Maeda Maki, Yamada Shunji, Iwata Kinuyo, Maeda Kei-ichiro, Tsukamura Hiroko

    BIOLOGY OF REPRODUCTION     page: 108 - 109   2008

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  136. Design of a Web community for female researchers Reviewed

    Zhou Wei, Jien Kato, Takami Yasuda, Shigeki Yokoi, Hiroko Tsukamura

    3rd International Conference on Innovative Computing Information and Control, ICICIC'08     2008

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    The number and percentage of female researchers in Japan is very low than other developed countries. How to give them effective support has becoming a noticeable topic in recently years. We design a web community for female researchers which has a community function to promote their communication, a role model function to encourage them to continue their research work. The study is ongoing and future plans are mentioned. © 2008 IEEE.

    DOI: 10.1109/ICICIC.2008.218

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  137. Estrogenic regulation of pubertal KiSS-1 mRNA expression in female rats Reviewed

    Yoshihisa Uenoyama, Kenji Takase, Motomichi Shimizu, Hiroko Tsukamura, Kei-ichiro Maeda

    BIOLOGY OF REPRODUCTION     page: 286 - 287   2008

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  138. Generation of specific antisera against N- and C-terminal peptides of goat metastin/kisspeptin Reviewed

    Ohkura Satoshi, Takase Kenji, Uenoyama Yoshihisa, Wakabayashi Yoshihiro, Ohsako Shunji, Tsukamura Hiroko, Maeda Kei-ichiro, Okamura Hiroaki

    BIOLOGY OF REPRODUCTION     page: 308 - 308   2008

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  139. Metastin/kisspeptin as a central regulator of reproductive axis Reviewed

    Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Brain Science   Vol. 34 ( 1 ) page: 18 - 28   2008

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    A number of evidences suggested that the population of metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) is involved in generating a GnRH surge to induce ovulation in rodents, and thus the target of estrogen positive feedback. The AVPV metastin/kisspeptin neuronal population is obvious in females, but few in males, suggesting that the absence of the surge generating mechanism or positive feedback action in males is due to the limited number of AVPV metastin/kisspeptin neuronal population. On the other hand, the arcuate nucleus (ARC) metastin/kisspeptin neuronal population might be involved in the tonic GnRH release. The ARC metastin/kisspeptin neurons show no sex difference in their expression, which is suppressed by gonadal steroids in both sexes. These facts suggest that ARC metastin/kisspeptin neurons are the target of estrogen negative feedback action on tonic gonadotropin-releasing hormone (GnRH) release. Thus, the peptide seems to be a central regulator of reproductive axis in both sexes of mammalian species including human.

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  140. Metastin/kisspeptin-GPR54 system regulating reproductive functions in mammals Reviewed

    Hiroko Tsukamura, Shunji Yamada, Tamanu Homma, Yoko Inamoto, Yoshihisa Uenoyama, Satoshi Ohkura, Naoko Inoue, Kei-ichiro Maeda

    BIOLOGY OF REPRODUCTION     page: 280 - 280   2008

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  141. Effects of neurokinin B and neurokinin 3 receptor antagonist on pulsatile LH secretion in female rats

    Noritake K., Sanbuissho A., Uenoyama Y., Tsukamura H., Maeda K.

    BIRTH DEFECTS RESEARCH PART A-CLINICAL AND MOLECULAR TERATOLOGY   Vol. 79 ( 5 ) page: 425 - 425   2007.5

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  142. Inhibition of metastin (kisspeptin-54)-GPR54 signaling in the arcuate nucleus-median eminence region during lactation in rats Reviewed

    S. Yamada, Y. Uenoyama, M. Kinoshita, K. Iwata, K. Takase, H. Matsui, S. Adachi, K. Inoue, K. I. Maeda, Hiroko Tsukamura

    Endocrinology   Vol. 148 ( 5 ) page: 2226 - 2232   2007.5

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    Follicular development and ovulation are suppressed during lactation in various mammalian species, mainly due to the suppression of pulsatile GnRH/LH secretion. Metastin (kisspeptin-54), a KiSS-1 gene product, is an endogenous ligand for GPR54, a G-protein-coupled receptor, and suggested to play a critical role in regulating the gonadal axis. The present study therefore aims to determine whether metastin (kisspeptin-54)-GPR54 signaling in discrete brain areas is inhibited by the suckling stimulus that causes suppression of LH secretion in lactating rats. Quantitative RT-PCR revealed that the KiSS-1 mRNA level was significantly lower in the arcuate nucleus (ARC)-median eminence region in lactating ovariectomized (OVX) and estrogen-treated OVX rats than in nonlactating controls. KiSS-1 mRNA in the anteroventral periventricular nucleus was kept at a low level in both lactating and nonlactating rats despite estrogen treatment. GPR54 mRNA levels were significantly lower in lactating than nonlactating rats in the anteroventral periventricular nucleus, but the levels in lactating mothers of the preoptic area and ARC-median eminence were comparable with nonlactating controls. Although KiSS-1 mRNA-expressing cells or metastin (kisspeptin-54) immunoreactivities were densely located in the ARC of nonlactating controls, few were found in the ARC of lactating OVX animals. Various doses of metastin (kisspeptin-54) (0.02, 0.2, and 2 nmol) injected into the third ventricle caused a significant increase in LH secretion in both lactating and nonlactating OVX rats, suggesting that lactating rats are responsive to metastin (kisspeptin-54) stimulus. Thus, the present study demonstrated that KiSS-1 mRNA/metastin (kisspeptin-54) expression is inhibited in the ARC by the suckling stimulus, suggesting that the inhibition is most probably involved in suppressing LH secretion in lactating rats. Copyright © 2007 by The Endocrine Society.

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  143. Expression of porcine FSHβ subunit promoter-driven herpes simplex virus thymidine kinase gene in transgenic rats Reviewed

    Li Yi Cai, Takako Kato, Kazumi Ito, Michie Nakayama, Takao Susa, Satoko Aikawa, Kei Ichiro Maeda, Hiroko Tsukamura, Akihiko Ohta, Shun Ichiro Izumi, Yukio Kato

    Journal of Reproduction and Development   Vol. 53 ( 2 ) page: 201 - 209   2007.4

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    A transgenic rat was established using the construct of porcine FSHβ subunit promoter, the -852/+10 bp region, fused to a Herpes simplex virus thymidine kinase (HSV-TK) gene. Integration of the transgene was confirmed by PCR of tail DNA. RT-PCR of total RNAs of the pituitary, gonad, cerebellum, liver, kidney, adrenal gland, prostate, and uterus revealed that FSHβ was only expressed in the pituitary. Analysis of the expression of reporter gene, HSV-TK, using two specific primer sets revealed that different transcripts were present in the pituitary and testis. The transcript initiated at the transcription initiation site of the porcine FSHβ gene was detected in the pituitary, and another within the TK gene was found in the testis, indicating ectopic testis-specific expression. Immunohistochemistry of the pituitary glands of the transgenic rats for FSH and HSV-TK demonstrated that the FSH-producing cells also produced HSV-TK. The results indicated that the -852/+10 bp region of the FSHβ promoter contains an element(s) that determines the tissue-specific expression. We succeeded in producing FSHβ promoter-driven HSV-TK transgenic rats and were the first time to do so using an animal other than the mouse. The transgenic rats show male infertility that involves abnormal spermatogenesis. We also observed a decrease in the weight of the testis and epididymis, and both motile and living spermatozoa were absent in the epididymis. Consequently, the FSHβ-HSV-TK transgenic rat will provide a useful model for studies on FSH function and male infertility.

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  144. Involvement of anteroventral periventricular metastin/kisspeptin neurons in estrogen positive feedback action on luteinizing hormone release in female rats Reviewed

    Sachika Adachi, Shunji Yamada, Yoshihiro Takatsu, Hisanori Matsui, Mika Kinoshita, Kenji Takase, Hitomi Sugiura, Tetsuya Ohtaki, Hirokazu Matsumoto, Yoshihisa Uenoyama, Hiroko Tsukamura, Kinji Inoue, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 53 ( 2 ) page: 367 - 378   2007.4

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    Metastin/kisspeptin, the KiSS-1 gene product, has been identified as an endogenous ligand of GPR54 that reportedly regulates GnRH/LH surges and estrous cyclicity in female rats. The aim of the present study was to determine if metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges. We demonstrated that preoptic area (POA) infusion of the anti-rat metastin/kisspeptin monoclonal antibody blocked the estrogen-induced LH surge, indicating that endogenous metastin/kisspeptin released around the POA mediates the estrogen positive feedback effect on GnRH/LH release. Metastin/kisspeptin neurons in the anteroventral periventricular nucleus (AVPV) may be responsible for mediating the feedback effect because the percentage of c-Fos-expressing KiSS-1 mRNA-positive cells to total KiSS-1 mRNA-positive cells was significantly higher in the afternoon than in the morning in the anteroventral periventricular nucleus (AVPV) of high estradiol (E 2)-treated females. The percentage of c-Fos-expressing metastin/kisspeptin neurons was not different between the afternoon and morning in the arcuate nucleus (ARC). Most of the KiSS-1 mRNA expressing cells contain ERα immunoreactivity in the AVPV and ARC. In addition, AVPV KiSS-1 mRNA expressions were highest in the proestrous afternoon and lowest in the diestrus 1 in females and were increased by estrogen treatment in ovariectomized animals. On the other hand, the ARC KiSS-1 mRNA expressions were highest at diestrus 2 and lowest at proestrous afternoon and were increased by ovariectomy and decreased by high estrogen treatment. Males lacking the surge mode of GnRH/LH release showed no obvious cluster of metastin/kisspeptin-immunoreactive neurons in the AVPV when compared with high E2-treated females, which showed a much greater density of these neurons. Taken together, the present study demonstrates that the AVPV metastin/kisspeptin neurons are a target of estrogen positive feedback to induce GnRH/LH surges in female rats.

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  145. Metastin/kisspeptin and control of estrous cycle in rats Reviewed

    Maeda Kei-Ichiro, Adachi Sachika, Inoue Kinji, Ohkura Satoshi, Tsukamura Hiroko

    REVIEWS IN ENDOCRINE & METABOLIC DISORDERS   Vol. 8 ( 1 ) page: 21 - 29   2007.3

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  146. Sexually dimorphic metastin neurons in medaka brain Reviewed

    Matsumoto Shinji, Akazome Yasuhisa, Yamamoto Naoyuki, Okubo Kataaki, Yamada Shunji, Tsukamura Hiroko, Maeda Kei-Ichiro, Oka Yoshitaka

    NEUROSCIENCE RESEARCH   Vol. 58   page: S222 - S222   2007

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  147. Acute lipoprivation suppresses pulsatile luteinizing hormone secretion without affecting food intake in female rats Reviewed

    Mohammad Shahab, Somchai Sajapitak, Hiroko Tsukamura, Mika Kinoshita, Shuichi Matsuyama, Satoshi Ohkura, Shunji Yamada, Yoshihisa Uenoyama, Helen I'Anson, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 52 ( 6 ) page: 763 - 772   2006.12

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    The present study examined the effect of acute lipoprivation on pulsatile luteinizing hormone (LH) secretion in both normal-fat diet, ad libitum-fed and fasted female rats. To produce an acute lipoprivic condition, mercaptoacetate (MA), an inhibitor of fatty acid oxidation, was administered intraperitoneally to ad libitum-fed or 24-h fasted ovariectomized (OVX) rats with or without an estradiol (E2) implant, that produces a negative feedback effect on LH pulses. The steroid treatment was performed to determine the effect of estrogen on lipoprivic changes in LH release, because estrogen enhances fasting- or glucoprivation-induced suppression of LH pulses. Pulsatile LH secretion was suppressed by MA administration in a dose-dependent manner in the ad libitum-fed OVX and OVX+E2 rats. LH pulses were more severely suppressed in the 24-h-fasted OVX and OVX+E2 rats compared to the ad libitum-fed rats. Estrogen slightly enhanced lipoprivic suppression but the effect was not significant. In the present study, increased plasma glucose and free-fatty acid concentrations may indicate a blockade of fatty acid metabolism by the MA treatment, but food intake was not affected by any of the MA doses. Acute vagotomy did not block lipoprivic suppression of LH pulses. Thus, the present study indicates that lipid metabolism is important for maintenance of normal reproductive function even in rats fed a normal-fat diet and lipoprivation may be more critical in fasted animals that probably rely more heavily on fatty acid oxidation to maintain appropriate metabolic fuel levels. In addition, failure of blockade of lipoprivic LH inhibition by vagotomy suggests that lipoprivic information resulting in LH suppression is not transmitted to the brain via the vagus nerve.

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  148. Metastin: A neuropeptide controlling reproductive functions Reviewed

    Hiroko Tsukamura, Kei-ichiro Maeda

    ZOOLOGICAL SCIENCE   Vol. 23 ( 12 ) page: 1143 - 1144   2006.12

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  149. Possible novel function of metastin neurons as dual neuromodulators in the vertebrate brain Reviewed

    Matsumoto Shinji, Yamamoto Naoyuki, Akazome Yasuhisa, Yamada Shunji, Tsukamura Hiroko, Maeda Kei-ichiro, Oka Yoshitaka

    ZOOLOGICAL SCIENCE   Vol. 23 ( 12 ) page: 1189 - 1189   2006.12

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  150. Temporal expression of estrogen receptor α in the hypothalamus and medulla oblongata during fasting: A role of noradrenergic neurons Reviewed International journal

    Beverly A.S. Reyes, Hiroko Tsukamura, Helen l'Anson, Maria Amelita C. Estacio, Kanjun Hirunagi, Kei Ichiro Maeda

    Journal of Endocrinology   Vol. 190 ( 3 ) page: 593 - 600   2006.9

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    Fasting-induced LH suppression is augmented by estrogen in female rats. We investigated the temporal changes in the number of estrogen receptor α (ERα)-immunoreactive (ir) cells in various brain regions in ovariectomized rats fasted for 6, 24, 30, and 48 h, commencing at 1300 h. We also determined the anatomical relationship of ERα immunoreactivity and dopamine-β-hydroxylase (DBH) neurons in the A2 region of the nucleus of the solitary tract (NTS) and the paraventricular nucleus (PVN). The number of ERα-ir cells significantly increased after 30 h from the onset of fasting in the PVN and NTS compared with the unfasted controls and was sustained until 48 h. In the A2 region of 48-h fasted rats, 46.75% DBH-ir cells expressed ERα, and this was significantly higher than in unfasted controls (8.16% DBH-ir cells expressed ERα). In the PVN, most ERα-ir neurons were juxtaposed with DBH-ir varicosities. These results suggest that ERα is expressed in specific brain regions at a defined time from the onset of fasting. In addition, the anatomical relationship of noradrenergic and ERα-ir neurons in the A2 region and PVN may suggest a role for estrogen in increasing the activity of noradrenergic neurons in the A2 region and enhancing sensitivity of the PVN to noradrenergic input arising from the lower brainstem and thereby augmenting the suppression of LH secretion during fasting. © 2006 Society for Endocrinology.

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  151. Metastin: a neuropeptide playing a central role regulating reproduction Reviewed

    Tsukamura H., Maeda K.

    REGULATORY PEPTIDES   Vol. 135 ( 3 ) page: 201 - 201   2006.8

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  152. Effects of exposure of rat dams to 1-bromopropane during pregnancy and lactation on growth and sexual maturation of their offspring Reviewed International journal

    Koichi Furuhashi, Junzoh Kitoh, Hiroko Tsukamura, Kei ichiro Maeda, Hailan Wang, Weihua Li, Sahoko Ichihara, Tamie Nakajima, Gaku Ichihara

    Toxicology   Vol. 224 ( 3 ) page: 219 - 228   2006.7

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    1-Bromopropane (1-BP) exhibits neuroreproductive toxicities in adult rats and humans. Here, we determined the effects of exposure of rat dams to 1-BP during pregnancy and lactation on the growth and sexual maturation of their offspring. In Experiment 1, 40 rats were exposed to 0, 100, 400 and 800 ppm 1-BP during pregnancy and lactation for 8 h/day. Ten rats that were not placed in chambers throughout the experiment served to observe the effect of separation of dams from offspring. In Experiment 2, three groups of 10 pregnant rats each were exposed to fresh air in three chambers and 10 other rats were exposed to 800 ppm 1-BP during pregnancy and lactation for 8 h/day. After delivery, offspring of the exposed and non-exposed dams were swapped so that they were nursed by the opposite dams. In Experiment 1, the survival rate and body weight of offspring were lower than the non-exposed in 1-BP dose-dependent manner. In Experiment 2, the survival rate and body weight of offspring (Group A) nursed by exposed dams and those (Group B) of exposed dams were significantly lower than non-exposed groups. The body weight of Group A was lower than that of Group B, although the two groups showed a significant equal decrease in the survival rate. The number of dead offspring from Group A was significantly higher. Our results indicate that exposure to 1-BP during pregnancy and lactation has comparable effects on survival rate, but exposure during lactation has a more adverse effect on growth of offspring than that during pregnancy. Moreover, exposure during lactation is associated with reduced early survival of third generation (F2) rats. © 2006 Elsevier Ireland Ltd. All rights reserved.

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  153. Neuroendocrine mechanism mediating energetic regulation of gonadotropin release in female rats

    Hiroko Tsukamura, Mika Kinoshita, Kei Ichiro Maeda

    Animal Science Journal   Vol. 77 ( 3 ) page: 259 - 265   2006.6

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    Energy level is a critical factor controlling gonadal activity at various phases of reproduction. A female rat model has revealed that fasting-induced luteinizing hormone (LH) suppression is mediated by a specific neural pathway, such as noradrenergic neurons originating in the A2 region and projecting to the hypothalamic paraventricular nucleus and corticotropin-releasing hormone neurons. The pathway is shared with that mediating glucoprivic suppression of LH pulses. Among the peripheral signals altered by energy deficiency, glucose could be a signal molecule conveying the peripheral information to the brain to regulate feeding and gonadotropin-releasing hormone/LH release through the noradrenergic pathway during undernutrition. The brain detects the energy availability to control feeding and reproductive function at various phases of an animal's life. It is most likely that the central glucose-sensing mechanism could be similar to the pancreatic one, involving a glucokinase-mediated process to detect glucose availability. Further studies are needed to elucidate the mechanism integrating the energy signals. © 2006 Japanese Society of Animal Science.

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  154. Erratum: The impact of stress on reproduction: Are glucocorticoids inhibitory or protective to gonadotropin secretion? (Endocrinology (2006) 147 (1085-1086)) Reviewed

    K. I. Maeda, H. Tsukamura

    Endocrinology   Vol. 147 ( 5 ) page: 2505   2006.5

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  155. Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats Reviewed

    B. A.S. Reyes, N. D. Bautista, N. C. Tanquilut, R. V. Anunciado, A. B. Leung, G. C. Sanchez, R. L. Magtoto, P. Castronuevo, H. Tsukamura, K. I. Maeda

    Journal of Ethnopharmacology   Vol. 105 ( 1-2 ) page: 196 - 200   2006.4

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    Momordica charantia and Andrographis paniculata are the commonly used herbs by the diabetic patients in Pampanga, Philippines. While the anti-diabetic potential of Momordica charantia is well established in streptozocin- or alloxan-induced diabetic animals, the anti-diabetic potential of Andrographis paniculata in alloxan-induced diabetic rat is not known. Neither the effects of these herbs on estrous cyclicity of alloxan-induced diabetic rats are elucidated. Thus, in these experiments, Momordica charantia fruit juice or Andrographis paniculata decoction was orally administered to alloxan-induced diabetic rats. Rats that were treated with Momordica charantia and Andrographis paniculata had higher body weight (BW) compared with diabetic positive control (P < 0.01) from day 22 to day 27 (D27) but exhibited lower BW than the non-diabetic control (P < 0.05). These rats had lower feed (P < 0.05) and liquid intakes (P < 0.01) compared with diabetic positive control from day 17 to D27, but similar with the non-diabetic control. The blood glucose levels in these groups were significantly reduced from day 12 to D27 compared with diabetic positive control (P < 0.01), however, comparable with non-diabetic control. The diabetic positive control had extended mean estrous cycles (8 days) compared to Momordica charantia and Andrographis paniculata-treated diabetic rats (5 days; P < 0.05). Our results suggest that the anti-diabetic potentials of Momordica charantia and Andrographis paniculata could restore impaired estrous cycle in alloxan-induced diabetic rats. © 2005 Elsevier Ireland Ltd. All rights reserved.

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  156. The impact of stress on reproduction: Are glucocorticoids inhibitory or protective to gonadotropin secretion? Reviewed

    Maeda K, Tsukamura H

    ENDOCRINOLOGY   Vol. 147 ( 3 ) page: 1085 - 1086   2006.3

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  157. Noradrenergic receptors in the bed nucleus of the stria terminalis in regulating pulsatile luteinizing hormone secretion in female rats

    Yamada S, Uenoyama Y, Maeda K, Tsukamura H

    JOURNAL OF REPRODUCTION AND DEVELOPMENT   Vol. 52 ( 1 ) page: 115 - 121   2006.2

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  158. Role of noradrenergic receptors in the bed nucleus of the stria terminalis in regulating pulsatile luteinizing hormone secretion in female rats Reviewed

    Shunji Yamada, Yoshihisa Uenoyama, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 52 ( 1 ) page: 115 - 21   2006.2

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    The bed nucleus of the stria terminalis (BNST) is one of the brain areas densely innervated by noradrenergic neurons originating in the brain stem. The present study aims to determine the role of noradrenergic receptors in the BNST in regulating pulsatile luteinizing hormone (LH) secretion in female rats. Ovariectomized (OVX) or estrogen-primed OVX (OVX+E2) rats received three 1-h-interval injections of 0.05 μmol of noradrenaline (NA), phenylephrine (α1-adrenergic receptor agonist), clonidine (α2-agonist), or isoproterenol (β-agonist) into the BNST. Injection of NA or α1-adrenergic agonist into the BNST strongly suppressed pulsatile LH secretion in OVX+E2 rats with a significant (P<0.05) decrease in the mean LH level for 3 h and LH pulse frequency, but α2- and β-agonists did not affect any of the LH pulse parameters. In OVX animals, α1- and α2- adrenergic agonists caused a significant change in LH pulse frequency and amplitude, respectively, though the effect was not as apparent as the NA- or α1-agonist-induced changes in OVX+E2 animals. These results indicate that NA inputs to the BNST suppress pulsatile LH secretion via α1-adrenergic receptors and that estrogen enhances this suppression.

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  159. Anti-diabetic potentials of Momordica charantia and Andrographis paniculata and their effects on estrous cyclicity of alloxan-induced diabetic rats. Reviewed

    Reyes, B. A. S., N. D. Bautista, N. C. Tanquilut, R. V. Anunciado, A. B. Leung, G. C. Sanchez, R.L. Magtoto, P.Castronuevo, Tsukamura, H., and Maeda, K.-I.

    Journal of Ethnopharmacology   Vol. 105   page: 196 - 200   2006

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  160. Acute Lipoprivation Suppresses Pulsatile Luteinizing Hormone Secretion without Affecting Food Intake in Female Rats. Reviewed

    Shahab,M., Sajapitak, S., Tsukamura H., Kinoshita M., Matsuyama S., Ohkura S., Yamada S., Uenoyama Y., I'Anson, H., and Maeda K.-I.

    Journal of Reproduction and Development, 52, 763-772.   Vol. 52   page: 763 - 772   2006

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  161. Temporal expression of estrogen receptor α in the hypothalamus and medulla oblongata during fasting: a role of noradrenergic neurons. Reviewed

    Reyes, B. A. S., Tsukamura, H., I'Anson, H., Estacio, M. A. C., Hirunagi, K., and Maeda, K.-I.

    Journal of Endocrinology   Vol. 190   page: 539 - 600   2006

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  162. Effects of exposure of rat dams to 1-bromopropane during pregnancy and lactation on growth and sexual maturation of their offspring. Reviewed

    Furuhashi, K., Kitoh, J., Tsukamura, H., Maeda, K.-I., Hailan, W., Weihua, L., Ichihara, S., Nakajima, T., and Ichihara, G.

    Toxicology   Vol. 224   page: 219 - 228   2006

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  163. Ketone body sensing cells in the lower brain stem to regulate food intake and reproductive functions

    Iwata Kinuyo, Kinoshita Mika, Sato Hiroaki, Tsukamura Hiroko, Maeda Kei-ichiro

    NEUROSCIENCE RESEARCH   Vol. 55   page: S226 - S226   2006

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  164. Delayed puberty in female rats by immunoneutralization of central metastin Reviewed

    Yoshihisa Uenoyama, Kenji Takase, Junya Hirata, Hiroko Tsukamura, Kei-ichiro Maeda

    NEUROSCIENCE RESEARCH   Vol. 55   page: S192 - S192   2006

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  165. Metastin expression in female rat brain during peripubertal period Reviewed

    Kenji Takase, Yoshihisa Uenoyama, Shunji Yamada, Hiroko Tsukamura, Kei-ichiro Maeda

    NEUROSCIENCE RESEARCH   Vol. 55   page: S192 - S192   2006

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  166. Metastin: A neuropeptide playing a central role in the regulation of ovulatory cycle Reviewed

    Hiroko Tsukamura, Kei-ichiro Maeda

    NEUROSCIENCE RESEARCH   Vol. 55   page: S46 - S46   2006

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  167. Involvement of central metastin in the regulation of preovulatory luteinizing hormone surge and estrous cyclicity in female rats Reviewed International journal

    Mika Kinoshita, Hiroko Tsukamura, Sachika Adachi, Hisanori Matsui, Yoshihisa Uenoyama, Kinuyo Iwata, Shunji Yamada, Kinji Inoue, Tetsuya Ohtaki, Hirokazu Matsumoto, Kei Ichiro Maeda

    Endocrinology   Vol. 146 ( 10 ) page: 4431 - 4436   2005.10

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    Ovulation is caused by a sequence of neuroendocrine events: GnRH and LH surges that are induced by positive feedback action of estrogen secreted by the mature ovarian follicles. The central mechanism of positive feedback action of estrogen on GnRH/LH secretion, however, is not fully understood yet. The present study examined whether metastin, the product of metastasis suppressor gene KiSS-1, is a central neuropeptide regulating GnRH/LH surge and then estrous cyclicity in the female rat. Metastin had a profound stimulation on LH secretion by acting on the preoptic area (POA), where most GnRH neurons projecting to the median eminence are located, because injection of metastin into the third ventricle or POA increased plasma LH concentrations in estrogen-primed ovariectomized rats. Metastin neurons were immunohistochemically found in the arcuate nucleus (ARC) to be colocalized with estrogen receptors with some fibers in the preoptic area (POA) in close apposition with GnRH neuronal cell bodies or fibers. Quantitative RT-PCR has revealed that KiSS-1 and GPR54 mRNAs were expressed in the ARC and POA, respectively. The blockade of local metastin action in the POA with a specific monoclonal antibody to rat metastin completely abolished proestrous LH surge and inhibited estrous cyclicity. Metastin-immunoreactive cell bodies in the ARC showed a marked increase and c-Fos expression in the early proestrus afternoon compared with the day of diestrus. Thus, metastin released in the POA is involved in inducing the pre-ovulatory LH surge and regulating estrous cyclicity. Copyright © 2005 by The Endocrine Society.

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  168. Activation of melanocortin receptors accelerates the gonadotropin-releasing hormone pulse generator activity in goats Reviewed International journal

    Shuichi Matsuyama, Satoshi Ohkura, Katsuyasu Sakurai, Hiroko Tsukamura, Kei Ichiro Maeda, Hiroaki Okamura

    Neuroscience Letters   Vol. 383 ( 3 ) page: 289 - 294   2005.8

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    The present study aims to elucidate whether the central melanocortin receptors [melanocortin-3 and -4 receptors (MC3/4-R)] are involved in regulating GnRH pulse generator activity in female goats. The GnRH pulse generator activity was electrophysiologically assessed at the intervals of characteristic increases in multiple-unit activity (MUA volleys) in the mediobasal hypothalamus. In ovariectomized goats, all doses (0.02, 0.2 and 2 nmol) of MT II, an MC3/4-R agonist, injected into the lateral ventricle significantly shortened MUA volley intervals. The duration of the period during which MT II accelerated MUA volleys was positively correlated with the dose of MT II injected. The stimulatory effect of MT II on the GnRH pulse generator activity was attenuated in the presence of estrogen. Intracerebroventricular injection of SHU9119, an MC3/4-R antagonist, significantly prolonged MUA volley intervals at 1 nmol. MT II (0.2 nmol)-induced acceleration of MUA volleys was partially blocked by the antagonism of MC3/4-R with pre-administered SHU9119 (1 nmol). The present findings demonstrate that MC3/4-R are involved in maintaining GnRH pulse generator activity in goats. © 2005 Elsevier Ireland Ltd. All rights reserved.

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  169. Simultaneous observation of the GnRH pulse generator activity and plasma concentrations of metabolites and insulin during fasting and subsequent refeeding periods in shiba goats Reviewed

    Shuichi Matsuyama, Satoshi Ohkura, Toru Ichimaru, Katsuyasu Sakurai, Hiroko Tsukamura, Kei Ichiro Maeda, Hiroaki Okamura

    Journal of Reproduction and Development   Vol. 50 ( 6 ) page: 697 - 704   2004.12

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    The time course of GnRH pulse generator activity and plasma concentrations of energy substrates and insulin were simultaneously observed in female goats during 4-day fasting and subsequent refeeding in the presence or absence of estrogen for a better understanding of the mechanism of energetic control of gonadotropin secretion in ruminants. The GnRH pulse generator activity was electrophysiologically assessed with the intervals of characteristic increases in multiple-unit activity (MUA volleys) in the mediobasal hypothalamus. In estradiol-treated ovariectomized (OVX+E2) goats, the MUA volley intervals increased as fasting progressed. Plasma concentrations of non-esterified fatty acid and ketone body increased, while those of acetic acid and insulin decreased during fasting. The MUA volley intervals and plasma concentrations of those metabolites and insulin were restored to pre-fasting levels after subsequent refeeding. In ovariectomized (OVX) goats, changes in plasma metabolites and insulin concentrations were similar to those in OVX+E2 goats, but the MUA volley intervals were not altered. The present results demonstrated that fasting suppressed GnRH pulse generator activity in an estrogen-dependent manner. Changes in plasma concentrations of energy substrates and insulin during fasting were associated with the GnRH pulse generator activity in the presence of estrogen, but not in the absence of the steroid in female goats.

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  170. Involvement of brainstem catecholaminergic inputs to the hypothalamic paraventricular nucleus in estrogen receptor α expression in this nucleus during different stress conditions in female rats Reviewed International journal

    Maria Amelita C. Estacio, Hiroko Tsukamura, Beverly A.S. Reyes, Yoshihisa Uenoyama, Helen I'Anson, Kei Ichiro Maeda

    Endocrinology   Vol. 145 ( 11 ) page: 4917 - 4926   2004.11

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    In the present study, we determined the involvement of brainstem catecholaminergic inputs to the paraventricular nucleus (PVN) on estrogen receptor α (ERα) expression in this nucleus during conditions of 48-h fasting, 2-deoxy-D-glucose (2DG)-induced acute glucoprivation and 1-h immobilization, in ovariectomized rats. Our approach was to examine the effect of lesioning catecholaminergic inputs to the PVN using DSAP [saporin-conjugated anti-DBH (dopamine-β-hydroxylase)]. Bilateral injection of DSAP into the PVN, 2 wk before stress, prevented fasting-, glucoprivation-, and immobilization-induced increase in ERα-immunopositive cells in the PVN. The DBH-immunoreactive (ir) terminals in the PVN were severely depleted by DSAP injection in all experimental groups. Among the brainstem noradreneregic cell groups examined, DBH-ir cell bodies were significantly reduced in the A2 region of all experimental groups treated with DSAP compared with the saporin- and vehicle-injected controls. PVN DSAP injection caused a small, but not significant, decrease in A1 DBH-ir cell bodies in fasted and immobilized rats, and a significant, but slight, reduction in A1 DBH-ir cell bodies of iv 2DG-injected rats compared with PVN vehicle-injected or PVN saporin-injected controls. The A6 DBH-ir cell bodies in all experimental groups treated with DSAP, saporin, or vehicle did not show any significant difference. These results suggest that the brainstem catecholaminergic inputs to the PVN, especially from the A2 cell group, may play a major role in mediating the induction of ERα expression in the PVN by metabolic stressors such as fasting, acute glucoprivation, and less specific stressors, such as immobilization, in female rats.

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  171. Prominent expression of spinocerebellar ataxia type-1 (SCA1) gene encoding ataxin-1 in LH-producing cells, LβT2 Reviewed

    Satoshi Ogawa, Satoko Aikawa, Takako Kato, Kyoko Tomizawa, Hiroko Tsukamura, Kei Ichiro Maeda, Nezka Petric, Folkmar Elsaesser, Yukio Kato

    Journal of Reproduction and Development   Vol. 50 ( 5 ) page: 557 - 563   2004.10

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    The LH-producing cell line, LβT2, and non LH-producing cell line, αT3-1 cells, established from a pituitary tumor, were employed for cDNA subtraction cloning to identify genes with expression unique to LH producing cells. Several cDNAs that code for known as well as for many unidentified clones were discovered. Most clones were the spinocerebellar ataxia type-1 (SCA1) gene encoding ataxin-1, the abnormality of which causes neurodegeneration and loss of cerebellar Purkinje cells. We examined whether the expression of SCA1 gene in LβT2 cells is related to hormone production. We also compared the expression of SCA1 with that in various other pituitary tumor derived cell lines, and confirmed the prominent expression of SCA1 in LβT2 cells. The effect of gonadal factor(s) for SCA1 gene expression was examined. The expression level in female rats was low and did not change during the estrus cycle, but increased significantly after ovariectomy and did not return to the normal level under low and high doses of estrogen. In the male pituitary SCA1 gene expression increased markedly after castration and was not decreased by estrogen or testosterone. The Ontogeny of SCA1 gene expression was investigated in porcine fetal and postnatal pituitaries and reveaed biphasic and sexually dimorphic expression. Transient expression of SCA1 gene was observed at fetal day 50 and 65 in males and day 40 in females, followed by a decline and increased expression before birth in both genders. Thus the expression of SCA1 gene is prominent in LH-producing cells and is not under direct control of gonadal factor(s) in both genders. In addition to the variable expression of SCA1 gene during the fetus period, the present results provide a novel aspect to the understanding of Boucher-Neuhauser syndrome (Ataxia Hypogonadism Choroidal Dystrophy).

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  172. Fourth ventricular alloxan injection suppresses pulsatile luteinizing hormone release in female rats Reviewed

    Mika Kinoshita, Helen I'Anson, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 50 ( 3 ) page: 279 - 285   2004.6

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    Previous studies have suggested the presence of a glucose-sensing mechanism in the hindbrain that appears to regulate reproductive function as well as feeding behavior. The ependymocytes lining the ventricular wall of the hindbrain showed immunoreactivities to pancreatic glucokinase (GK), a key enzyme for glucose sensing in pancreatic B cells. Our goal in the present study was to test whether the GK-immunopositive ependymocytes in the wall of the fourth cerebroventricle (4V) play a role in regulating gonadal activity. Our approach was to determine the effect of injecting alloxan, a GK inhibitor, into the 4V on pulsatile luteinizing hormone (LH) secretion. Estrogen-primed ovariectomized rats received an injection of alloxan (10 or 20 μg/animal) into the 4V and blood samples were collected every 6 min for 3 h for measurement of blood LH, corticosterone and glucose levels. Pulsatile LH secretion was suppressed after alloxan injection and all pulse parameters were significantly (P<0.05) inhibited by 20 μg alloxan. Plasma corticosterone levels were increased significantly (P<0.05) by 20 μg alloxan, suggesting that LH pulse suppression by alloxan may be at least partly mediated by activation of the hypothalamo-pituitary-adrenal axis. The present results suggest that acute suppression of GK activity in the hindbrain inhibits pulsatile LH secretion in female rats, and supports the idea that GK-immunopositive ependymocytes may sense glucose levels in the cerebrospinal fluid and play a role in regulation of LH secretion.

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  173. In vitro increase in intracellular calcium concentrations induced by low or high extracellular glucose levels in ependymocytes and serotonergic neurons of the rat lower brainstem Reviewed International journal

    Ryutaro Moriyama, Hiroko Tsukamura, Mika Kinoshita, Hirokatsu Okazaki, Yukio Kato, Kei Ichiro Maeda

    Endocrinology   Vol. 145 ( 5 ) page: 2507 - 2515   2004.5

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    Pancreatic glucokinase (GK)-like immunoreactivities are located in ependymocytes and serotonergic neurons of the rat brain. The present study investigated in vitro changes in intracellular calcium concentrations ([Ca 2+]i) in response to low (2 mM) or high (20 mM) extracellular glucose concentrations in isolated cells from the wall of the central canal (CC), raphe obscurus nucleus (ROb), ventromedial hypothalamus (VMH), and lateral hypothalamic area (LHA) in male rats. An increase in [Ca 2+], was found in cells from the CC (21.1% or 9.8% of ependymocytes), ROb (10.9% or 14.5% of serotonergic neurons), VMH (7.8% and 25.2% of neurons), and LHA (20% or 15.7% of neurons), when extracellular glucose levels were changed from 10 to either 2 or 20 mM, respectively. Most of the ependymocytes and serotonergic neurons responding to the glucose changes were immunoreactive to the anti-GK in the CC (96.8% for low glucose and 100% for high glucose) and ROb (100% for low and high glucose). The [Ca2+]i increase was blocked with calcium-free medium or L-type calcium channel blocker. Cells with an increase in [Ca2+]i in response to low glucose did not respond to high glucose and vice versa. Inhibition of GK activity with acute alloxan treatment blocked low or high glucose-induced [Ca 2+]i increases in most GK-immunoreactive cells from the CC or ROb. The glucose-sensitive [Ca2+]i increase in neurons of the VMH and LHA was also alloxan-sensitive, but no cells taken from the VMH and LHA were immunoreactive to the antibody used. The present study further indicates that ependymocytes of the CC and serotonergic neurons in the ROb are also sensitive to the changes in extracellular glucose in a GK-dependent manner, but that the subtype of GK in these cells could be different from that in the VMH and LHA.

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  174. A rat model for the energetic regulation of gonadotropin secretion: Role of the glucose-sensing mechanism in the brain Reviewed

    M. Kinoshita, R. Moriyama, H. Tsukamura, K. I. Maeda

    Domestic Animal Endocrinology   Vol. 25 ( 1 ) page: 109 - 120   2003.7

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    Energy availability has been considered to regulate gonadal activity by modulating the release of gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) at various reproductive phases, such as lactation and puberty in domestic as well as wild animals. Experimental models with rats and sheep have demonstrated that fasting or glucoprivation suppresses pulsatile LH release. From those experiments, the information on energy deficiency is considered to be detected by specific central sensors and conveyed to the hypothalamus to regulate LH release as well as food intake. Noradrenergic neurons, originating in the medulla oblongata and projecting to the hypothalamic paraventricular nucleus (PVN), is reported to be one of the pathways mediating the response of LH release to energy deficiency. The other component is considered to be an energy-sensing mechanism in the brain. Glucose or other oxidizable fuels may function as a metabolic signal to regulate LH release. Previous studies suggest the presence of a glucose-sensing mechanism in the rat hindbrain. From our previous results in the rat, the ependymocytes lining the wall of the cerebroventricle could possibly serve as a glucose sensor to regulate GnRH/LH release. Greater understanding of the nature of the energy-sensing mechanism in the brain will contribute to the nutritional manipulation of reproductive performance in domestic animals in various conditions. © 2003 Elsevier Inc. All rights reserved.

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  175. Glucoprivation-induced fos expression in the hypothalamus and medulla oblongata in female rats Reviewed

    Ryutaro Moriyama, Beverly A.S. Reyes, Hiroko Tsukamura, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 49 ( 2 ) page: 151 - 7   2003.4

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    Glucoprivation induced by 2-deoxy-D-glucose (2DG) suppresses pulsatile luteinizing hormone (LH) secretion in female rats. The suppression is enhanced in the presence of estrogen. In the present study, 2DG-induced Fos expression was examined in the solitary tract nucleus (NTS), hypothalamic paraventricular nucleus (PVN), raphe obscurus nucleus (ROb) and raphe pallidus nucleus (RPa), which have been previously suggested to be involved in glucoprivation-induced suppression of LH secretion in female rats. Ovariectomized (OVX) or estrogen-primed ovariectomized (OVX+E2) rats were injected intravenously with 2DG (400 mg/kg BW). The brain was removed 1 h after the injection. The number of Fos-like-immunoreactive (Fos-li) cells in the PVN and NTS was significantly increased in OVX+E2 rats compared with control groups, but did not show a significant increase in the OVX group. Few Fos-li cells were observed in the ROb and RPa in all groups. All of the Fos-li cells in the PVN and NTS were neurons because they had immunoreactivities to microtubule-associated protein 2. Some Fos-li cells (8.3%) had tyrosine hydroxylase-like immunoreactivities in the NTS in 2DG-treated OVX+E2 rats. These results suggest that neurons in the PVN and NTS are involved in the estrogen-dependent neural cascade mediating glucoprivic suppression of LH secretion in female rats.

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  176. Exposure to 1-bromopropane causes ovarian dysfunction in rats. Reviewed

    Yamada T, Ichihara G, Wang H, Yu X, Maeda K, Tsukamura H, Kamijima M, Nakajima T, Takeuchi Y

    Toxicological sciences : an official journal of the Society of Toxicology   Vol. 71 ( 1 ) page: 96 - 103   2003.3

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  177. Lactation-associated infertility in Japanese monkeys (Macaca fuscata) during the breeding season Reviewed

    Masahiro Kondo, Hisashi Kishi, Chihiro Kojima, Wanzhu Jin, Juri Suzuki, Keiko Shimizu, Mariko Itoh, Satoshi Ohkura, Hiroko Tsukamura, Kei Ichiro Maeda, Gen Watanabe, Kazuyoshi Taya

    Zoo Biology   Vol. 22 ( 1 ) page: 65 - 76   2003

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    To investigate the endocrine factors in Japanese monkeys (Macaca fuscata) responsible for the suppression of the estrous cycle during the first reproductive season after delivery (150-360 days postpartum), peripheral blood was taken to measure plasma concentrations of follicle stimulating hormone (FSH), luteinizing hormone (LH), progesterone, estradiol-17β, immunoreactive (ir)-inhibin, and cortisol. The results demonstrated that during the breeding season of lactating Japanese monkeys, circulating concentrations of FSH (1.7-2.7 ng/ml), LH (308.5-461.0 pg/ml), estradiol-17β (<62.6 pg/ml), and progesterone (145.0-453.0 pg/ml) remained low and were similar to the nadir levels observed during both the normal menstrual cycles and the nonbreeding season. Concentrations of irinhibin, which is secreted from both follicles and corpus luteum in female Japanese monkeys, were also low (300.5-585.0 pg/ml). This strongly suggests that no follicular development occurs during lactation. Serum concentrations of cortisol (261.0-519 ng/ml) were higher during lactation than during the nonbreeding season. Since babies were often seen suckling their mothers during the study, the results indicate that the increased cortisol levels were associated with suckling-induced secretion of corticotrophin-releasing hormone (CRH) and adrenocorticotropic hormone (ACTH). The results of this study indicate that a long period of postpartum infertility in lactating Japanese monkeys, with apparent inhibition of follicle growth and anovulation, is due to weak gonadotropin stimulation, which may occur as the result of a suckling stimulus. © 2003 Wiley-Liss, Inc.

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  178. 自動連続採血装置を用いた経時的な血中ホルモン濃度の測定

    "吉田恭子,木下美香,生村和子,西野博仁,束村博子"

    アニテックス   Vol. 14   page: 49 - 54   2002.1

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  179. The arcuate nucleus mediates facilitating effect of estrogen on glutamate-induced in vitro GnRH release from nerve terminals of female rats Reviewed

    Kumiko Murahashi, Shinji Tsukahara, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 48 ( 2 ) page: 183 - 188   2002.1

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    It is well accepted that glutamate stimulates in vivo and in vitro gonadotropin-releasing hormone (GnRH) and/or luteinizing hormone (LH) release. The present study aimed to determine whether the arcuate nucleus (ARC) has a role in exerting the modulating effect of estrogen on GnRH response to glutamate. The effects of estrogen on glutamate-induced in vitro GnRH release from either the ARC-median eminence (ME) or ME fragment were examined in female rats. Both high and low doses of estradiol-17 β treatment in ovariectomized OVX animals enhanced glutamate-induced GnRH release from the ARC-ME fragment but not from the ME fragment. This suggests that the ARC mediates the facilitating effect of estrogen on glutamate-induced GnRH release from the ARC-ME. The facilitating effect of estrogen was also observed on GnRH release from the ARC-ME treated with selective excitatory amino acid agonists, i.e., N-methyl-D-aspartate (NMDA), kainate, and α-amino-3-hydroxy-5-methyl-4- isoxazole propionic acid. These results suggest that the ARC plays an important role in facilitating estrogen actions on GnRH response to glutamate via both NMDA and non-NMDA receptors. The estrogen-induced enhancement of GnRH secretory response to glutamate in the ARC-ME region could partly contribute to the induction of preovulatory GnRH/LH surge.

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  180. Glucoprivation increases estrogen receptor α immunoreactivity in the brain catecholaminergic neurons in ovariectomized rats Reviewed

    Beverly A.S. Reyes, Maria Amelita C. Estacio, Helen I'Anson, Hiroko Tsukamura, Kei ichiro Maeda

    Neuroscience Letters   Vol. 299 ( 1-2 ) page: 109 - 112   2001.2

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    Estrogen-dependent enhancement of glucoprivic-induced luteinizing hormone (LH) suppression is hypothesized to be due to increased estrogen receptor α (ERα)-immunoreactive (ir) cells in specific brain nuclei in a manner similar to fasting. ERα expression in various brain areas was determined in ovariectomized rats after systemic 2-deoxy-D-glucose (2DG)-induced glucoprivation. Expression of ERα in catecholaminergic neurons in the lower brainstem was also examined. ERα-ir cells increased in hypothalamic paraventricular and periventricular nuclei, and A1 and A2 regions of the brainstem 1 h after 2DG injection. The percentage of ERα in the tyrosine hydroxylase (TH)- and dopamine-β-hydroxylase (DBH)-ir neurons was higher in A1 and A2 regions of 2DG-treated rats, but the number of TH- and DBH-ir cells did not change. Thus, 2DG induces ERα expression in specific brain nuclei and expression of ERα in catecholaminergic neurons of the brainstem indicates a role for estrogen in activating those neurons projecting to the hypothalamic paraventricular nucleus to suppress LH secretion during glucoprivation. © 2001 Elsevier Science Ireland Ltd.

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  181. Novel estrogen feedback associated with fasting-induced suppression of luteinizing hormone secretion in female rats Reviewed

    Hiroko Tsukamura, Maria Amelita C. Estacio, Beverly A.S. Reyes, Kei Ichiro Maeda

    Neuroplasticity, Development, and Steroid Hormone Action     page: 221 - 232   2001.1

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    © 2002 by CRC Press LLC. It has been shown that estrogen regulates gonadotropin-releasing hormone (GnRH)/luteinizing hormone (LH) secretion by both positive and negative feedback action at hypothalamic and pituitary levels. Basal levels of circulating estrogen associated with immature follicles act to suppress GnRH/LH secretion, whereas the high level of estrogen associated with mature follicles stimulates secretion, eventually leading to the GnRH/LH surge and then ovulation. Thus, the brain receives information regarding follicular development from circulating estrogen levels to maintain GnRH/LH concentrations at an appropriate level and to keep follicular development and the occurrence of ovulation at the right phase of the estrous cycle.

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  182. Effect of fasting on c-fos expression in the hypothalamic nuclei and nucleus of the solitary tract in male rats: Time course study and the role of testosterone Reviewed

    Beverly A.S. Reyes, Sakiko Yamada, Maria Amelita C. Estacio, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 47 ( 1 ) page: 53 - 62   2001

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    We have shown that 48-h fasting suppresses luteinizing hormone (LH) secretion in female rats which is enhanced by an estrogenic milieu and mediated by noradrenergic neurons. A similar fasting protocol yielded a suppression of LH secretion in male rats in a testosterone-dependent manner. In this experiment, we intended to identify specific nuclei in the hypothalamus and caudal brainstem that are activated during fasting for 6, 24, 30 or 48 h in castrated male rats with or without chronic testosterone treatment. Fasting started at 1300 h (lights-off at 1900 h). In testosterone-treated castrates, Fos-like-immunoreactive (FL-ir) cells were significantly increased in the paraventricular nucleus, A2 region of the nucleus of the solitary tract, supraoptic nucleus and amygdala 6 h after the onset of fasting but not 24, 30 or 48 h after the onset. On the other hand, FL-ir cells were not significantly different in those areas among fasted castrates compared with unfasted controls. In the A2 region of testosterone-treated castrates, tyrosine hydroxylase- and dopamine-β-hydroxylaseimmunoreactive (TH-ir, DBH-ir) cells did not exhibit Fos-like immunoreactivity (FLI). Our results suggest that the absence of food may activate neurons in discrete hypothalamic and brainstem nuclei in male rats at the beginning of fasting and this activation requires an androgenic milieu. The absence of FLI in TH- or DBH-ir cells in the A2 region would indicate that transmitter systems other than catecholaminergic neurons may be involved during the very early stage of 48-h fasting-induced suppression of LH secretion.

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  183. Non-metabolic and metabolic factors causing lactational anestrus: Rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother Reviewed

    Hiroko Tsukamura, Kei Ichiro Maeda

    Progress in Brain Research   Vol. 133   page: 187 - 205   2001

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    Follicular development and ovulation are strongly inhibited during lactation. Administration of a high dose of estrogen induces luteinizing hormone (LH) surges in ovariectomized lactating rats, suggesting that brain mechanisms regulating cyclic LH release remain intact in lactating mothers. On the other hand, tonic LH release is profoundly suppressed in lactating rats. This suggests that lactational anestrus is mainly due to suppression of the mechanism regulating pulsatile gonadotropin-releasing hormone secretion in the hypothalamus, which is responsible for follicular development and steroid production. Both metabolic and non-metabolic factors are involved in suppressing pulsatile LH secretion throughout lactation in rats. During the first half of lactation, pulsatile LH secretion is strongly suppressed, even if milk production is attenuated by pharmacological blockade of prolactin secretion in ovariectomized lactating rats. Pulsatile LH release quickly recovers by removing pups or blocking neuronal input by hypothalamic deafferentation during the period. These data suggest that the suckling stimulus itself is responsible for suppression of LH release during the first half of lactation. During the second half of lactation, negative energy balance, which is caused by the milk production, appears to play a dominant role in suppressing LH secretion. Blockade of milk production by inhibiting prolactin release causes a gradual increase in LH release even if the vigorous suckling stimulus by foster pups remains. In conclusion, the suckling stimulus itself predominantly suppresses LH pulses during the first half of lactation and metabolic factors take over the role of the suckling stimulus during the second half of lactation.

    DOI: 10.1016/S0079-6123(01)33014-5

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  184. Central, but not peripheral, glucose-sensing mechanisms mediate glucoprivic suppression of pulsatile luteinizing hormone secretion in the sheep Reviewed

    Satoshi Ohkura, Tomomi Tanaka, Shoji Nagatani, David C. Bucholtz, Hiroko Tsukamura, Kei Ichiro Maeda, Douglas L. Foster

    Endocrinology   Vol. 141 ( 12 ) page: 4472 - 4480   2000.12

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    Changes in glucose availability are proposed to modulate pulsatile GnRH secretion, and at least two anatomical sites, the liver and hindbrain, may serve as glucose sensors. The present study determined the relative importance of these putative glucose-sensing areas in regulating pulsatile LH secretion in the sheep. Our approach was to administer the antimetabolic glucose analog, 2-deoxy-D-glucose (2DG) into either the hepatic portal vein or the fourth ventricle in gonadectomized females in which LH pulse frequency was high. In the first study, a catheter was placed in the ileocolic vein to determine the effects of local injection of 2DG into the hepatic portal system on the release of LH. After monitoring the pattern of LH secretion for 4 h, 2DG (250 mg/kg) was infused (500 μl/min) into the liver for 2 h. For comparison, animals were also given the same dose of 2DG into a jugular vein for 2 h. Administration of 2DG into either the hepatic portal or jugular vein reduced LH pulse frequency to the same extent. Infusion of the lower dose (50 mg/kg) locally into the hepatic portal vein did not affect plasma LH profiles. Collectively, these results are interpreted to indicate that the liver does not contain special glucose-sensing mechanisms for the glucoprivic suppression of LH pulses. In the second study, 2DG (5 mg/kg) was infused (50 μl/min) for 30 min into the fourth ventricle or lateral ventricle. During the subsequent 4-h sampling period, pulsatile LH secretion was significantly suppressed, but there was no significant difference in LH pulse frequency between sites of infusion. Peripheral 2DG concentrations were not detectable after either fourth or lateral ventricle infusions, indicating that the 2DG had acted centrally to suppress LH pulses. Plasma cortisol concentrations increased more in animals infused with 2DG into the fourth ventricle than in those infused into the lateral ventricle, suggesting that 2DG infused into lateral ventricle is transported caudally into the fourth ventricle and acts within the area surrounding the fourth ventricle. Overall, these findings suggest that an important glucose-sensing mechanism is located circumventricularly in the fourth ventricle. Moreover, the liver does not appear to play an important role in detecting glucoprivic action of 2DG to suppress pulsatile LH secretion.

    DOI: 10.1210/endo.141.12.7853

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  185. Intracerebroventricular administration of melanin-concentrating hormone suppresses pulsatile luteinizing hormone release in the female rat Reviewed

    H. Tsukamura, R. C. Thompson, S. Tsukahara, S. Ohkura, F. Maekawa, R. Moriyama, Y. Niwa, D. L. Foster, K. I. Maeda

    Journal of Neuroendocrinology   Vol. 12 ( 6 ) page: 529 - 534   2000.6

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    Melanin-concentrating hormone (MCH) has been reported to be involved in the regulation of feeding behaviour in rats and mice. Because many neuropeptides that influence ingestive behaviour also regulate reproductive function, the present study was designed to determine if central administration of MCH changes pulsatile secretion of luteinizing hormone (LH) in the rats. Wistar-Imamichi strain female rats were ovariectomized and implanted with oestradiol to produce a moderate inhibitory feedback effect on LH release. The effects of i.c.v. injections of MCH on LH release were examined in freely moving animals. Blood samples were collected every 6 min for 3 h through an indwelling cannula. After 1 h of sampling, MCH (0.1, 1 or 10 μg/animal) or vehicle (saline) was injected into the third cerebroventricle. Because MCH is also reported to affect the hypothalamo-pituitary-adrenal (HPA) axis, which in turn, can influence reproductive function, plasma corticosterone concentrations were determined in the same animals at 30-min intervals during the first and last hours and every 12 min during the second hour of the 3-h sampling period. When expressed as per cent changes, mean plasma LH concentrations after MCH administration were significantly lower in the animals injected with all doses of the peptide compared with vehicle-treated animals; LH pulse frequency was significantly lowered by 1 μg of MCH. Per cent changes in mean plasma corticosterone levels were not significantly affected by MCH administration. These results in oestradiol-treated ovariectomized rats indicate that central MCH is capable of inhibiting pulsatile LH secretion. We have previously shown that 48-h fasting suppresses pulsatile LH release in the presence of oestrogen. Take together, these results raise the possibility that MCH could play a role in mediating the suppression of LH secretion during periods of reduced nutrition.

    DOI: 10.1046/j.1365-2826.2000.00482.x

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  186. Central action of insulin regulates pulsatile luteinizing hormone secretion in the diabetic sheep model Reviewed

    Tomomi Tanaka, Shoji Nagatani, David C. Bucholtz, Satoshi Ohkura, Hiroko Tsukamura, Kei Ichiro Maeda, Douglas L. Foster

    Biology of Reproduction   Vol. 62 ( 5 ) page: 1256 - 1261   2000.5

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    This study tested the hypothesis that central mechanisms regulating luteinizing hormone (LH) secretion are responsive to insulin. Our approach was to infuse insulin into the lateral ventricle of six streptozotocin- induced diabetic sheep in an amount that is normally present in the CSF when LH secretion is maintained by peripheral insulin administration. In the first experiment, we monitored cerebrospinal fluid (CSF) insulin concentrations every 3-5 h in four diabetic sheep given insulin by peripheral injection (30 IU). The insulin concentration in the CSF was increased after insulin injection, and there was a positive relationship between CSF and plasma concentrations of insulin (r = 0.80, P < 0.01). In the second experiment, peripheral insulin administration was discontinued, and the sheep received either an intracerebroventricular (i.c.v.) infusion of insulin (12 mU/day in 2.4 ml saline) or saline (2.4 ml/day) for 5 days (n = 6) in a crossover design. The dose of insulin (i.c.v.) was calculated to approximate the increase in CSF insulin concentration found after peripheral insulin treatment. To monitor LH secretory patterns, blood samples were collected by jugular venipuncture at 10-min intervals for 4 h on the day before and 5 days after the start of i.c.v. insulin infusion. To monitor the increase in CSF insulin concentrations, a single CSF sample was collected one and four days after the start of the central infusion. The i.c.v. insulin infusion increased CSF insulin concentrations above those in saline-treated animals (P < 0.05) and maintained them at or above the peak levels achieved after peripheral insulin treatment. Central insulin infusion did not affect peripheral (plasma) insulin or glucose concentrations. LH pulse frequency in insulin-treated animals was greater than that in saline-treated animals (3.5 ± 0.2 vs. 2.3 ± 0.3 pulses/4 h, P < 0.01), but it was less than that during peripheral insulin treatment (4.8 ± 0.2 pulses/4 h, P < 0.01). Our findings suggest that physiologic levels of central insulin supplementation are able to increase pulsatile LH secretion in diabetic sheep with low peripheral insulin. These results are consistent with the notion that central insulin plays a role in regulating pulsatile GnRH secretion.

    DOI: 10.1095/biolreprod62.5.1256

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  187. Peripheral or central administration of motilin suppresses LH release in female rats: A novel role for motilin Reviewed

    H. Tsukamura, S. Tsukahara, F. Maekawa, R. Moriyama, B. A.S. Reyes, T. Sakai, Y. Niwa, D. L. Foster, K. I. Maeda

    Journal of Neuroendocrinology   Vol. 12 ( 5 ) page: 403 - 408   2000.5

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    Motilin is secreted in a clear episodic pattern during fasting or during the interdigestive phase, but feeding promptly stops this secretory pattern, and plasma concentrations of motilin decrease. We have previously determined that fasting markedly suppresses pulsatile luteinizing hormone (LH) secretion in female rats in the presence of oestrogen. In the present study, we wished to learn if motilin may mediate the fasting-induced suppression of LH secretion by determining the effects of motilin administration on LH release and on food intake. Intravenous (i.v.) injection of motilin (37 nmol/rat) suppressed LH release and significantly decreased mean LH concentrations both in ovariectomized (OVX) and oestradiol-implanted ovariectomized (OVX + E2) rats. Food intake was significantly increased by i.v. motilin injection in OVX rats, but not in OVX + E2 rats. It is likely that motilin inhibits LH release via inhibition of the gonadotrophin-releasing hormone (GnRH)-releasing mechanism at the hypothalamic level, because motilin (3.7 nmol/rat) also suppressed LH secretion when centrally administered, and because LH release in i.v. motilin-treated rats increased in response to exogenous GnRH. These results suggest that motilin may be a peripheral signal for the suppression of LH secretion through central sensors.

    DOI: 10.1046/j.1365-2826.2000.00467.x

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  188. Regulation of pulsatile luteinizing hormone secretion by insulin in the diabetic male lamb Reviewed

    David C. Bucholtz, Alejandra Chiesa, William N. Pappano, Shoji Nagatani, Hiroko Tsukamura, Kei Ichiro Maeda, Douglas L. Foster

    Biology of Reproduction   Vol. 62 ( 5 ) page: 1248 - 1255   2000.5

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    This study tested the hypothesis that LH secretion is modulated by insulin and that the responsiveness to hypoinsulinemia is enhanced by sex steroids. The model was the developing male lamb (12-26 wk of age) rendered diabetic by chemically induced necrosis of insulin-secreting tissue (streptozotocin). Our approach was to monitor LH secretion under diabetic conditions, with or without insulin supplementation, either in the presence or in the absence of gonadal steroids. The first experiment determined if chronic insulin supplementation could sustain LH secretion in diabetic lambs. After documentation of the induced diabetic condition, twice-daily treatment with a long-acting insulin preparation (Lente) minimized diabetes-induced hyperglycemia, sustained growth, and maintained LH pulse frequency at levels comparable to pre-diabetic conditions. A second experiment evaluated the acute regulation of LH secretion by insulin. Twenty-four hours of insulin withdrawal decreased LH pulse frequency, increased circulating glucose levels, increased the concentration of plasma non-esterified fatty acids (NEFAs), and increased urinary output of ketones. LH pulse frequency continued to decline after 96 h of insulin withdrawal. By contrast, 24 h of insulin re-supplementation increased LH pulse frequency, reduced circulating glucose and NEFA concentrations, decreased plasma cortisol, and reduced urinary output of ketones. After 96 h of insulin re-supplementation, LH pulse frequency increased further, to levels comparable with those before insulin withdrawal. A third experiment determined if the effects of insulin withdrawal on LH secretion are influenced by the presence of gonadal steroids. The same individuals were treated with a physiologic dose of estradiol (Silastic capsule, s.c.) and subsequently monitored for changes in LH secretion in the presence and in the absence of exogenous insulin. Prior to insulin withdrawal, estradiol decreased both LH pulse frequency and pulse amplitude. Moreover, after 96 h of insulin withdrawal, estradiol potentiated the decline in LH pulse frequency (47% reduction in LH pulse frequency in the presence of estradiol versus 26% reduction in LH pulse frequency in the absence of estradiol). These findings support the contention that insulin and/or insulin-dependent changes in glucose availability modulate LH(GnRH) pulse frequency, and that such effects are potentiated by, but not dependent upon, gonadal steroids.

    DOI: 10.1095/biolreprod62.5.1248

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  189. Fasting-induced changes in pulsatile Luteinizing Hormone (LH) secretion in male rats: The role of testosterone and the hypothalamic paraventricular nucleus Reviewed

    Hiroko Tsukamura, Sakiko Yamada, Kei Ichiro Maeda

    Journal of Reproduction and Development   Vol. 46 ( 4 ) page: 227 - 234   2000.4

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    We have previously shown that 48-h fasting profoundly suppresses pulsatile LH secretion in female rats in the presence of estrogen, and that the paraventricular nucleus (PVN) is an estrogen action site mediating this inhibition. The present study determined whether fasting suppresses pulsatile LH secretion in male rats in a testosterone-dependent manner, and whether the PVN is involved in the fasting-induced changes in pulsatile LH release. Mean LH concentrations and baseline levels of LH pulses were significantly reduced by 48-h fasting in castrated males implanted with various length (6, 12, and 24 mm) of subcutaneous testosterone implants. LH pulse frequency was significantly lower in fasted rats with a 24-mm testosterone implant compared with unfasted controls. On the contrary, mean LH levels and the amplitude and baseline of LH pulses were significantly increased by fasting in castrated rats without testosterone treatment. PVN lesions partially blocked the inhibitory effect of fasting on LH release in the testosterone-implanted rat model. In addition, local implantation of testosterone or estradiol into the PVN reversed fasting-induced increase in both mean LH levels and the pulse amplitude in castrated males, but did not cause a further suppression of these pulse parameters. These results suggest that testosterone is required to suppress LH pulses during fasting in the male rat. The PVN may mediate, at least partly, the fasting-induced inhibition of LH secretion, and is not the single steroid feedback site mediating the fasting-induced suppression of LH secretion in the male.

    DOI: 10.1262/jrd.46.227

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  190. Localization of glucokinase-like immunoreactivity in the rat lower brain stem: For possible location of brain glucose-sensing mechanisms Reviewed

    Fumihiko Maekawa, Yukiyasu Toyoda, Norihiro Torii, Ichitomo Miwa, Robert C. Thompson, Douglas L. Foster, Shinji Tsukahara, Hiroko Tsukamura, Kei Ichiro Maeda

    Endocrinology   Vol. 141 ( 1 ) page: 375 - 384   2000.4

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    Pancreatic glucokinase (GK) is considered an important element of the glucose-sensing unit in pancreatic β-cells. It is possible that the brain uses similar glucose-sensing units, and we employed GK immunohistochemistry and confocal microscopy to examine the anatomical distribution of GK-like immunoreactivities in the rat brain. We found strong GK-like immunoreactivities in the ependymocytes, endothelial cells, and many serotonergic neurons. In the ependymocytes, the GK-like immunoreactivity was located in the cytoplasmic area, but not in the nucleus. The GK-positive ependymocytes were found to have glucose transporter-2 (GLUT2)-like immunoreactivities on the cilia. In addition, the ependymocytes had GLUT1-like immunoreactivity on the cilia and GLUT4-like immunoreactivity densely in the cytoplasmic area and slightly in the plasma membrane. In serotonergic neurons, GK-like immunoreactivity was found in the cytoplasm and their processes. The present results raise the possibility that these GK-like immunopositive cells comprise a part of a vast glucose-sensing mechanism in the brain.

    DOI: 10.1210/endo.141.1.7234

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  191. Reproductive toxicity of 1-bromopropane, a newly introduced alternative to ozone layer depleting solvents, in male rats Reviewed

    Gaku Ichihara, Xiaozhong Yu, Junzoh Kitoh, Nobuyuki Asaeda, Toshihiko Kumazawa, Hisakazu Iwai, Eiji Shibata, Tetsuya Yamada, Hailan Wang, Zhenlin Xie, Kei Ichiro Maeda, Hiroko Tsukamura, Yasuhiro Takeuchi

    Toxicological Sciences   Vol. 54 ( 2 ) page: 416 - 423   2000.4

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    1-Bromopropane has been newly introduced as an alternative to ozone- depleting solvents. We aimed to clarify its dose-dependent reproductive toxicity in male rats. Thirty-six Wistar male rats were randomly divided into 4 groups of 9. The groups were exposed to 200, 400, or 800 ppm 1-bromopropane or only fresh air, 8 h per day for 12 weeks. Epididymal sperm indices were evaluated after a 12-week exposure. The testes, epididymides, seminal vesicle, prostate, and other organs were weighed and examined histopathologically. Spermatogenic cells, in stage VII seminiferous tubules, and retained spermatids, at the basal region of stages IX-XI seminiferous epithelium, were counted. Plasma testosterone levels were measured by radioimmunoassay. The testicular weight did not significantly change, but the weight of epididymides, seminal vesicle, and prostate dose-dependently decreased. The weight of seminal vesicle decreased significantly at the lowest concentration of 200-ppm and over. 1-Bromopropane induced a dose- dependent decrease in the epididymal sperm count and in motility, as well as an increase in tailless sperm and sperm with an immature head shape. The spermatogonia, preleptotene spermatocytes, pachytene spermatocytes, and round spermatids did not decrease significantly at stage VII. Retained, elongated spermatids near the basement membrane at the postspermiation stages IX-XI increased dose-dependently. Plasma testosterone levels significantly decreased at the 800-ppm dosage. 1-Bromopropane caused failure of spermiation. Its reproductive toxicity is different from that of 2- bromopropane, which specifically impairs spermatogonia. Thus, this solvent may have serious reproductive toxic effects in men, and should be used very cautiously in the workplace.

    DOI: 10.1093/toxsci/54.2.416

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  192. Erratum: Reproductive toxicity of 1-bromopropane, a newly introduced alternative to ozone layer depleting solvents, in male rats (Toxicology Sciences (2000) 54 (416-423)) Reviewed

    G. Ichihara, X. Yu, J. Kitoh, N. Asaeda, T. Kumazawa, H. Iwai, E. Shibata, T. Yamada, H. Wang, Z. Xie, K. I. Maeda, H. Tsukamura, Y. Takeuchi

    Toxicological Sciences   Vol. 55 ( 2 )   2000

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  193. Prevention of inhibitory effect of dorsal raphe nucleus lesions on ovulation and LH surge by 5-HT 2A/2C receptor agonists in female rats Reviewed

    Fumihiko Maekawa, Shinji Tsukahara, Hiroko Tsukamura, Kei Ichiro Maeda, Korehito Yamanouchi

    Neuroscience Research   Vol. 35 ( 4 ) page: 291 - 298   1999.12

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    In order to investigate the role of the dorsal raphe nucleus and the serotonergic system in the regulation of ovulation, the number of ova and plasma luteinizing hormone (LH) concentrations were measured in female rats after making lesions in this nucleus (DRL) and/or treatment with 5-hydroxytryptamine (5-HT) receptor agonists or antagonists. DRL or sham lesion was made on the afternoon of proestrous (12:00-14:00 h) under ether anesthesia and the number of ova in the oviduct was counted on the next estrous and diestrous morning. In some animals, blood samples were taken via the atrial cannula during the proestrous evening for the radioimmunoassay of LH. All intact control and sham-operated females ovulated and plasma LH increased between 19:00 and 21:00 h. In contrast, ovulation was seen in only 36% of DRL rats. LH surge did not occur in this group. However, 80% of DRL rats ovulated after treatment with (±)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane hydrochloride [(±)-DOI; a 5-HT 2A/2C receptor agonist] at 15:00 h on proestrous day. LH surge was also observed in the DRL rats with (±)-DOI. On the other hand, only 8% of DRL rats ovulated after treatment with buspirone (5-HT 1A receptor agonist). Furthermore, when mianserin (5-HT 2A/2C receptor antagonist) was administered at 16:00 h on proestrous day, ovulation was not seen in all rats without DRL. These results suggest that the dorsal raphe nucleus plays an important role in induction of LH surge and ovulation and the 5-HT 2A/2C receptor system is involved in this mechanism. Copyright (C) 1999 Elsevier Science Ireland Ltd.

    DOI: 10.1016/S0168-0102(99)00090-5

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  194. Effect of corticotropin-releasing hormone antagonist on oestrogen-dependent glucoprivic suppression of luteinizing hormone secretion in female rats Reviewed

    S. Tsukahara, H. Tsukamura, D. L. Foster, Kei Ichiro Maeda

    Journal of Neuroendocrinology   Vol. 11 ( 2 ) page: 101 - 105   1999.4

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    Pharmacological reduction of glucose availability with 2-deoxyglucose (2DG) suppresses pulsatile luteinizing hormone (LH) secretion in rats and growth-retarded lambs. Gonadal steroids enhance the glucoprivic suppression of LH secretion in rats. The present study determined if corticotropin-releasing hormone (CRH) plays a role in mediating oestrogen-dependent and -independent glucoprivic suppression of LH secretion. The study was conducted in ovariectomized (OVX) rats some of which received Silastic implants containing oestradiol-17β (OE2) dissolved in peanut oil at 20 μg/ml to produce a physiological plasma level of OE2 (30 pg/ml). Seven days after ovariectomy, the rats were stereotaxically implanted with a guide cannula into the third cerebral ventricle. Seven days later, blood samples were collected through an indwelling atrial cannula every 6 min for 3 h for LH pulse determination. After the first hour of blood sampling, a CRH antagonist, [D-Phe12, Nle21,38]hCRF-(21-41), or vehicle was injected into the third cerebral ventricle through the implanted cannula before 2DG administration through the indwelling atrial cannula. Pulsatile LH secretion was suppressed by 2DG (200 mg/kg b.w.) in the vehicle-treated rats bearing OE2 implants. The CRH antagonist (5.65 nmol) blocked the suppressive effect of 2DG on pulsatile LH secretion in the OE2treated OVX animals. On the other hand, in the absence of oestrogen, the effect of a twice greater dose of 2DG (400 mg/kg b.w.) was not blocked by five times greater amount of CRH antagonist (28.3 nmol). These results suggest the mechanisms mediating glucoprivic suppression of LH secretion involve two components: one is oestrogen-dependent and the other oestrogen-independent. CRH may be involved in the oestrogen-dependent component of glucoprivic suppression of LH secretion but not the oestrogen-independent one.

    DOI: 10.1046/j.1365-2826.1999.00312.x

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  195. Morphological characterization of relationship between gap junctions and gonadotropin releasing hormone nerve terminals in the rat median eminence Reviewed

    Shinji Tsukahara, Fumihiko Maekawa, Hiroko Tsukamura, Kanjun Hirunagi, Kei Ichiro Maeda

    Neuroscience Letters   Vol. 261 ( 1-2 ) page: 105 - 108   1999.4

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    The present study aimed to reveal possible morphological relationships between gonadotropin-releasing hormone (GnRH) nerve terminals and gap junctions in the median eminence. Coronal brain sections from castrated male rats were dual immunostained with GnRH and either connexin 26, 32, or 43, and examined by confocal laser microscopy. Connexin 43-immunoreactive puncta were distributed between GnRH-immunoreactive fibers, and some of them were colocalized with GnRH-immunoreactivities. Dual immunostaining with connexin 43 and glial fibrillary acidic protein revealed that most of the puncta were located in astrocytes. At the immunoelectron microscopic level, connexin 43- immunoreactivities were mainly located on the plasma membranes of glial-like processes. Few connexin 26- or connexin 32-immunoreactivities were found in the median eminence. The present results indicate the possibility that gap junctions play a role in the GnRH release at the median eminence.

    DOI: 10.1016/S0304-3940(99)00017-8

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  196. Excitatory amino acids act on the median eminence nerve terminals to induce gonadotropin-releasing hormone release in female rats Reviewed

    Shin Ichi Kawakami, Masumi Ichikawa, Kumiko Murahashi, Kanjun Hirunagi, Hiroko Tsukamura, Kei Ichiro Maeda

    General and Comparative Endocrinology   Vol. 112 ( 3 ) page: 372 - 382   1998.12

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    The present study is designed to examine the terminal regulation of gonadotropin-releasing hormone (GnRH) release by excitatory amino acids in the median eminence of ovariectomized (OVX) rats. In in vitro experiments, median eminence tissues were superfused in the medium containing glutamate or excitatory amino acid agonists, such as N-methyl-D,L-aspartate or kainate. These drugs induced a Ca2+-dependent GnRH release from median eminence fragments. The agonists also stimulated GnRH release from superfused synaptosome prepared from the median eminence tissues in a Ca2+-dependent manner. In the immunocytochemical study, immunoreactivity for glutamate or its ionotropic receptor subtypes, such as NR1, GluR1, GluR2/3, GluR6/7, and KA2, was examined in the median eminence of OVX rats under electron microscopy. Immunoreactivities for glutamate or its receptor subtypes were observed on the nerve terminals, most of which were located in close proximity to the other nerve terminals without forming synaptic contacts. In addition, quite a few synaptic contacts which were immunopositive for GluR1, GluR2/3, KA2, or glutamate were found in this area. The present results indicate that excitatory amino acids stimulate GnRH release by acting at the nerve terminals of the median eminence in a Ca2+-dependent manner in the absence of gonadal steroid. The effect of excitatory amino acids in this area might be mediated by glutamate receptors mainly in nonsynaptic fashion, such as by volume transmission.

    DOI: 10.1006/gcen.1998.7140

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  197. Inhibitory effect of neural transections of dorsal raphe nucleus on induction of nocturnal prolactin surge by vaginal stimulation in ovariectomized rats Reviewed

    Fumihiko Maekawa, Shinji Tsukahara, Hiroko Tsukamura, Kei Ichiro Maeda, Korehito Yamanouchi

    Brain Research   Vol. 813 ( 1 ) page: 195 - 199   1998.11

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    The effect of complete (CC), anterior (AC) or posterior (PC) cut of the dorsal raphe nucleus (DRn) on induction of the nocturnal prolactin (PRL) surge by electrical vaginal stimulation (VS) was investigated in ovariectomized rats. Plasma level of PRL was measured by radioimmunoassay before and after VS. The data revealed that PRL levels increased in early morning on the day following VS in the rats without brain surgery or with sham-operation. In contrast, the nocturnal PRL surge did not occur in the CC, AC, or PC rats. These results suggest that both the anterior and the posterior fibers of the DRn plays an important role in induction of nocturnal PRL surge by VS in ovariectomized rats.

    DOI: 10.1016/S0006-8993(98)01019-1

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  198. Glucose availability modulates the timing of the luteinizing hormone surge in the ewe Reviewed

    Christopher L. Medina, Shoji Nagatani, Tiffany A. Darling, David C. Bucholtz, Hiroko Tsukamura, Kei Ichiro Maeda, Douglas L. Foster

    Journal of Neuroendocrinology   Vol. 10 ( 10 ) page: 785 - 792   1998.10

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    To determine if glucose availability modulates the timing of the positive feedback action of oestrogen on gonadotropin secretion, we monitored the estradiol-induced luteinizing hormone (LH) surge in sheep (n = 5/group) made transiently hypoglycemic by insulin. Experiment 1 determined an effective insulin treatment, one which would depress tonic LH secretion. Two injections of insulin (5 IU/kg iv) 4 h apart were found to induce extended hypoglycemia (10-13 h) and to decrease the LH pulse frequency for 8 h (5.0 ± 0.32 pulses/4 h before versus 2.5 ± 0.34 pulses/4 h after insulin; P < 0.05; mean ± SEM). Using this same paradigm, experiment 2 determined the influence of the transient hypoglycemia on the LH surge mechanism. In control sheep, estradiol (subcutaneous implants at hour 0) evoked an LH surge with a latency period of 12.4 ± 0.5 h. When insulin was administered either before (hours -4 and 0) or after the estradiol stimulus (hours 4 and 8, or 12 and 16), the onset of the LH surge was delayed to 29.0 ± 2.4 h (average of all three time groups, P < 0.05). Infusion of glucose from hours 12-30, along with insulin, prevented hypoglycemia and restored the normal timing of the oestrogen-induced LH surge to that of controls (15.4 ± 0.93 h, P > 0.05). These findings suggest that not only is the tonic mode of LH secretion sensitive to metabolic fuel availability, but the surge mode of LH secretion is as well.

    DOI: 10.1046/j.1365-2826.1998.00264.x

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  199. Evidence for GnRH regulation by leptin: Leptin administration prevents reduced pulsatile LH secretion during fasting Reviewed

    Shoji Nagatani, Padma Guthikonda, Robert C. Thompson, Hiroko Tsukamura, Kei Ichiro Maeda, Douglas L. Foster

    Neuroendocrinology   Vol. 67 ( 6 ) page: 370 - 376   1998.6

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    Administration of leptin during undernutrition improves reproductive function, but whether this occurs at the level of the brain, pituitary, or gonads is not yet clear. The present study tested the hypothesis that one important mechanism is the control of pulsatile gonadotropin-releasing hormone (GnRH) secretion. Our approach was to determine if leptin could prevent the marked suppression of pulsatile luteinizing hormone (LH) secretion which occurs during fasting. Leptin (3 μg/g i.p.; three times/48 h) or vehicle was administered during a 48-hour fast in adult ovariectomized and estrogen-treated ovariectomized rats (n = 5-7/group). LH was measured in blood samples collected every 6 min for 2 h before and after fasting. In vehicle-treated animals, plasma insulin and leptin levels decreased after fasting. As expected, the LH purse frequency also decreased markedly. When circulating leptin remained artificially elevated during fasting, the suppression of LH pulse frequency did not occur. Leptin treatment maintained a high LH pulse frequency in the presence or absence of estrogen. The finding that leptin modulates LH pulse frequency indicates that this fat-derived hormone conveys information about nutrition to mechanisms which regulate pulsatile gonadotropin-releasing hormone secretion. Because this occurs in the absence of estrogen, the mechanism does not necessarily involve modulation of negative feedback.

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  200. Glial and neuronal localization of neuronal nitric oxide synthase immunoreactivity in the median eminence of female rats Reviewed

    Shin Ichi Kawakami, Masumi Ichikawa, Makoto Yokosuka, Hiroko Tsukamura, Kei Ichiro Maeda

    Brain Research   Vol. 789 ( 2 ) page: 322 - 326   1998.4

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    Localization of neuronal nitric oxide synthase-immunoreactivity (nNOS- IR) in the median eminence of female rats (n = 4) was examined by electron microscopy to explore the possibility that nitric oxide is involved in the terminal regulation of neurosecretory peptides such as GnRH. Under light microscopy, a dense distribution of nNOS-IR was observed in this region. Electronmicroscopically, nNOS-IR was found in glial elements and nerve terminals containing dense-core vesicles. We also found a few nNOS- immunopositive synapses, in which intense immunoreactivity was found on the postsynaptic density and mitochondrial membrane. The localization of nNOS-IR in nerve terminals and glial elements in the median eminence might indicate that nNOS plays a role in regulating the release of neurosecretory peptide.

    DOI: 10.1016/S0006-8993(97)01561-8

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  201. 周排卵期の神経内分泌

    束村博子

    Journal of Reproduction and Development   Vol. 44   page: 81-90   1998.4

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  202. ストレス反応における性ステロイドフィードバックメカニズム

    前多敬一郎・束村博子

    "脳とステロイドホルモン,神経研究の進歩"   Vol. 42   page: 624-635   1998.4

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  203. Evidence for terminal regulation of GnRH release by excitatory amino acids in the median eminence in female rats: A dual immunoelectron microscopic study Reviewed

    Shin Ichi Kawakami, Kanjun Hirunagi, Masumi Ichikawa, Hiroko Tsukamura, Kei Ichiro Maeda

    Endocrinology   Vol. 139 ( 3 ) page: 1458 - 1461   1998.4

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    The present study was designed to determine whether excitatory amino acids directly act on the gonadotropin-releasing hormone (GnRH) nerve terminals to release the peptide. The median eminence taken from ovariectomized rats was dual immunostained with GnRH and ionotropic glutamate receptor subtypes (NR1, GluR1, GluR2/3, GluR6/7 and KA2), and their colocalization was examined under electron microscopy. The connection of fibers immunopositive for GnRH and glutamate was also examined. Of the glutamate receptor subtypes, NR1- and KA2-immunoreactivities were colocalized with GnRH-immunoreactivity in nerve terminals of the median eminence. In addition, some glutamate-immunopositive nerve terminals were shown to abut the many GnRH-immunopositive nerve terminals. No synaptic contacts were observed on these immunopositive nerve terminals. These results suggest that GnRH release is regulated at the GnRH nerve terminals by excitatory amino acids in a nonsynaptic manner in the median eminence.

    DOI: 10.1210/endo.139.3.5979

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  204. Energetic depeency of the LH surge system in the female sheep.

    "Medina, C.L., Darling, T.A., Nagatani, S., Bucholtz, D.C., Tsukamura, H., Maeda, K.-I. and Foster, D.L.,"

    Journal of Neuroeocrinology   Vol. 10   page: 785-792   1998.1

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  205. Estrogen modulates effects of glutamate on in vitro gonadotropin-releasing hormone release by altering nitric oxide action in female rats.

    "Tsukahara, S., Tsukamura, H. and Maeda, K.-I.,"

    Journal of Reproduction a Development   Vol. 44   page: 399-405   1998.1

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  206. Increase in in vivo glutamate release in the mediobasal hypothalamus during progesterone-enhanced LH surge in estrogen-primed ovariectomized rats Reviewed

    Kumiko Murahashi, Shoji Nagatani, Kei Ichiro Maeda, Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 44 ( 2 ) page: 135 - 140   1998.1

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    Progesterone has a facilitating effect on luteinizing hormone (LH) surges induced by estrogen in ovariectomized (OVX) rats. The aim of the present study was to elucidate the involvement of excitatory amino acids such as glutamate and aspartate, and noradrenaline (NA) in the mediobasal hypothalamus/median eminence (MBH) region in a progesterone-enhanced LH surge. Ovariectomized animals were implanted with a Silastic tubing containing crystalline estradiol (E2) for 2 days, and some of them received sc injection of progesterone (4 mg) at 0900 h on the day of sampling. The MBH was perfused using the push-pull perfusion method to determine the levels of glutamate, aspartate, glycine, glutamine, and NA during the LH surge. Blood samples were collected through an atrial cannula to determine plasma LH levels. In animals treated with both E2 and progesterone, levels of glutamate and glutamine significantly (P<0.01) increased simultaneously 1 to 2 h before the peak of LH surge, whereas those levels did not significantly change by E2 treatment alone. Levels of aspartate, glycine and NA showed no significant changes during steroid(s)-induced LH surges. These results suggest that the facilitating effect of progesterone on estrogen-induced LH surges might be mediated, at least in part, by glutamate released at the MBH where the majority of LHRH nerve terminals are distributed.

    DOI: 10.1262/jrd.44.135

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  207. Ovarian toxicity of 2-bromopropane in the non-pregnant female rat Reviewed

    Michihiro Kamijima, Gaku Ichihara, Junzoh Kitoh, Hiroko Tsukamura, Kei Ichiro Maeda, Xiaozhong Yu, Zhenlin Xie, Tamie Nakajima, Nobuyuki Asaeda, Naomi Hisanaga, Yasuhiro Takeuchi

    Journal of Occupational Health   Vol. 39 ( 2 ) page: 144 - 149   1997.4

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    A cluster of patients with amenorrhea, oligospermia and anemia were found among workers in an electronics factory in the Republic of Korea. 2-Bromopropane was suspected to cause the disorders. This study aimed to clarify its ovarian toxicity in the virgin rat. Female Wistar rats were daily exposed to 0, 100, 300, or 1,000 ppm 2-bromopropane for eight hours a day for 9 weeks. During the experimental period, vaginal smears were taken everyday to monitor ovarian cyclicity. Tissues were histopathologically examined and plasma concentrations of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined at the end of experiment. The vaginal smear test showed that the number of normal cycles decreased significantly both in the 300 and 1,000 ppm groups. The histopathological examination revealed dose-dependent ovarian follicle atresia accompanied by a decreased number of normal antral and growing follicles in the 300 and 1,000 ppm groups. Especially, in the ovaries of rats with persistent estrous smears in the 1,000 ppm group, most of the follicles were atretic and there were no newly formed corpora lutea. There still remained normal antral follicles and corpora lutea in the ovaries of the remaining rats of the group and of the 300 ppm group with constant diestrous and occasional estrous smears. Hormonal in LH or FSH concentrations between any groups. The results showed that 2-bromopropane has ovarian toxicity in rats, indicating that the secondary amenorrhea in human cases was due to 2-bromopropane exposure.

    DOI: 10.1539/joh.39.144

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  208. 飢餓ストレスと生殖機能

    前多敬一郎・束村博子

    運動生化学   Vol. 9   page: 11-19   1997.1

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  209. Disruption in Ovarian cyclicity due to 2-bromopropane in the rat Reviewed

    Michihiro Kamijima, Gaku Ichiiiara, Yu Xiaozhong, X. I.E. Zhenlin, Junzoh Krroh, Hiroko Tsukamura, Kei Ichiro Maeda, Tamie Nakajima, Nobuyuki Asaeda, Naomi Hisanaga, Yasuhiro Takeuchi

    Journal of Occupational Health   Vol. 39 ( 1 ) page: 3 - 4   1997

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    DOI: 10.1539/joh.39.3

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  210. Paraventricular norepinephrine release mediates glucoprivic suppression of pulsatile luteinizing hormone secretion Reviewed

    Shoji Nagatani, Hiroko Tsukamura, Kumiko Murahashi, David C. Bucholtz, Douglas L. Foster, Kei Ichiro Maeda

    Endocrinology   Vol. 137 ( 8 ) page: 3183 - 3186   1996.8

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    Restriction of glucose availability by 2-deoxyglucose (2DG) suppresses pulsatile LH release. The aim of the present study was to determine whether norepinephrine (NE) release in the paraventricular nucleus (pVN) is involved in the glucoprivic suppression of LH secretion in ovariectomized rats. Twelve days after ovariectomy, animals were stereotaxically implanted with a guide cannula for microdialysis in the PVN. Two days later, the PVN was perfused continuously with Ringer's solution or Ringer's solution containing a catecholamine synthesis inhibitor, α-methyl-p-tyrosine (100 μM), through a microdialysis probe inserted in the guide cannula 2 h before the beginning of sampling, which lasted 3 h. Blood samples were collected every 6 min through an atrial cannula, and dialysates were collected every 20 min. One hour after the beginning of sampling, 2DG (400 mg/kg BW) was administered iv through the atrial cannula. Paraventricular NE levels significantly increased immediately after 2DG injection (P < 0.05), and both mean LH concentrations and the frequency of LH pulses decreased. By contrast, when α-methyl-p-tyrosine was administered into the PVN, 2DG did not produce an increase in paraventricular NE, and no depression of LH secretion occurred. These results suggest that the PVN mediates the glucoprivic suppression of LH pulses via the release of NE.

    DOI: 10.1210/endo.137.8.8754737

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  211. Novel estrogen feedback sites associated with stress-induced suppression of luteinizing normone secretion in female rats Reviewed

    Kei Ichiro Maeda, Shoji Nagatani, Maria A. Estacio, Hiroko Tsukamura

    Cellular and Molecular Neurobiology   Vol. 16 ( 3 ) page: 311 - 324   1996.6

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    1. The fasting-induced suppression of LH secretion is totally dependent on steroidal milieu because the suppression is observed only in intact or ovariectomized estrogen-primed rats but not in ovariectomized animals. The following neural pathway mediating fasting-induced suppression of LH secretion has been suggested by a series of experiment: A neural signal emanating from the stomach during fasting reaches the medulla oblongata via afferent vagal nerve so as to activate the noradrenergic system projecting to the PVN: this results in an increased CRH release, and in turn the suppression of the LHRH release and then LH release. Estrogen seems to activate the neural pathway by acting on somewhere in the pathway. 2. We found that the paraventricular nucleus of the hypothalamus (PVN) and A2 region of the medulla oblongata is the estrogen feedback sites associated the dependence of the fasting-induced suppression of LH secretion on estrogen. The estrogen feedback action on the PVN does not involve an increase in norepinephrine release in the PVN. In addition, we also found that estrogen receptors are increased in the PVN and A2 region by acute fasting. Therefore, the following hypothesis is proposed: fasting first induces an transient increase in the activity of noradrenergic system at the beginning of the first dark phase after the food deprivation; this activation results in an increase in estrogen receptors in the PVN and A2 region; the increase in estrogen receptors leads to an increase in the sensitivity of noradrenergic systems to the neural inputs associated with fasting to these nuclei. 3. The response of the reproductive activity to various external stimuli including stress is modulated by ovarian steroids. The estrogen feedback action on the PVN and A2 is totally different from the so-called 'negative feedback action' of estrogen that is for monitoring the ovarian condition. The novel estrogen feedback action may alter the response of neurons regulating gonadal axis to the signal associated with environmental cues such as stress.

    DOI: 10.1007/BF02088098

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  212. Effect of fasting and immobilization stress on estrogen receptor immunoreactivity in the brain in ovariectomized female rats Reviewed

    Maria Amelita C. Estacio, Sakiko Yamada, Hiroko Tsukamura, Kanjun Hirunagi, Kei Ichiro Maeda

    Brain Research   Vol. 717 ( 1-2 ) page: 55 - 61   1996.4

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    The present study examined the effect of 48-h fasting and 1-h immobilization on estrogen receptor immunoreactivity in selected hypothalamic areas and the nucleus of the solitary tract (NTS) in ovariectomized rats. Fasting induced an increase in ER-immunoreactive cells in the paraventricular nucleus (PVN), periventricular nucleus (PeVN) and NTS compared with the unfasted control group. Similarly, immobilization caused an increase in ER-positive cells in the same areas, PVN, PeVN and NTS, versus the non-immobilized group. There was no significant increase in the number of ER-immunoreactive cells in the preoptic area (POA), arcuate nucleus (ARC) or ventromedial hypothalamic nucleus (VMH) following fasting and immobilization. Our previous work in ovariectomized rats with estrogen microimplants in the brain revealed that the PVN and A2 region of the NTS are the feedback sites of estrogen in activating the neural pathway to suppress pulsatile LH secretion during 48-h fasting. The result in the food-deprived rats suggests that estrogen modulation of the suppression of LH secretion during fasting is partly due to the increase in estrogen receptors in the PVN and A2 region. The physiological significance of the increase in neural ER following immobilization remains to be elucidated.

    DOI: 10.1016/0006-8993(96)00022-4

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  213. Vagus nerve mediates the increase in estrogen receptors in the hypothalamic paraventricular nucleus and nucleus of the solitary tract during fasting in ovariectomized rats Reviewed

    Maria Amelita C. Estacio, Hiroko Tsukamura, Sakiko Yamada, Shinji Tsukahara, Kanjun Hirunagi, Kei Ichiro Maeda

    Neuroscience Letters   Vol. 208 ( 1 ) page: 25 - 28   1996.4

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    The effect of total subdiaphragmatic vagotomy on estrogen-receptor immunoreactivity (ERIR) in the paraventricular nucleus (PVN) and nucleus of the solitary tract (NTS) was examined in fasted ovariectomized rats to clarify the peripheral inputs mediating fasting-induced increase in ERIR in these two nuclei. Vagotomy abolished the effect of 48-h fasting on the expression of ER in these two areas. The result indicates that the neural signal(s) that increase the expression of ER in the PVN and A2 region of the NTS following 48-h fasting is transmitted through the vagus. The involvement of the vagus in the fasting-induced increase in ER in the PVN and A2 region may also be the same neural pathway involved in the suppression of pulsatile luteinizing hormone secretion in fasted female rats.

    DOI: 10.1016/0304-3940(96)12534-9

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  214. Reduction of glucose availability suppresses pulsatile luteinizing hormone release in female and male rats

    Nagatani S, Bucholtz DC, Murahashi K, Estacio MAC, Tsukamura H, Foster DL, Maeda KI

    ENDOCRINOLOGY   Vol. 137 ( 4 ) page: 1166 - 1170   1996.4

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  215. A rapid suppressive effect of estrogen in the paraventricular nucleus on pulsatile LH release in fasting-ovariectomized rats Reviewed

    Shoji Nagatani, Hiroko Tsukamura, Kumiko Murahashi, Kei Ichiro Maeda

    Journal of Neuroendocrinology   Vol. 8 ( 4 ) page: 267 - 273   1996.4

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    The paraventricular nucleus (PVN) and A2 are novel estrogen feedback sites where estrogen may modulate the neural response to adrenergic inputs during fasting. In the present study, the effects of local estradiol (E2) perfusion through a microdialysis probe placed in the PVN or A2 on pulsatile luteinizing hormone (LH) secretion and on norepinephrine (NE) release in the PVN were examined in 48-h fasting ovariectomized (OVX) rats to determine whether local estrogen administered in the PVN or A2 rapidly inhibits LH secretion during fasting and whether this inhibition is mediated by an increase of NE release in the PVN. Five days after ovariectomy, animals (n = 5 per group) stereotaxically implanted with a guide cannula for microdialysis in the PVN (experiment 1) or both PVN and A2 (experiment 2) were deprived of food for 48 h. Blood samples and dialysates were then collected every 6 min for 3 h and every 12 min (experiment 1) or 20 min (experiment 2) for 3 h, respectively. The PVN or A2 was perfused with E2 (5 ng/ml in artificial cerebrospinal fluid) through a microdialysis probe after the first hour of sampling. E2 perfusion in the PVN caused a rapid and significant suppression of mean plasma LH levels and LH pulse frequency in fasting rats but no changes in unfasting animals. NE release in the PVN was not affected by the local E2 perfusion of the PVN in either fasting or unfasting groups. This perfusion in A2, however, did not cause any apparent changes in plasma LH and perfusate NE levels in the PVN and A2. The present results indicate that estrogen feedback action at the PVN suppresses LH secretion rapidly during fasting and does not involve an increase of NE release in the PVN.

    DOI: 10.1046/j.1365-2826.1996.04573.x

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  216. Reduction of glucose availability suppresses pulsatile luteinizing hormone release in female and male rats Reviewed

    Shoji Nagatani, David C. Bucholtz, Kumiko Murahashi, Maria A.C. Estacio, Hiroko Tsukamura, Douglas L. Foster, Kei Ichiro Maeda

    Endocrinology   Vol. 137 ( 4 ) page: 1166 - 1170   1996.4

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    Glucose availability controls reproductive activity through modulation of LH secretion. The aim of the present study was to determine whether the glucoprivic suppression is potentiated by gonadal steroids and if glucoprivic suppression of pulsatile LH release is sexually differentiated. Pulsatile LH secretion was examined in rats after peripheral (jugular) administration of the competitive inhibitor of glycolysis, 2-deoxyglucose (2DG). Fourteen days after gonadectomy, blood samples were collected every 6 min for 3 h. One hour after the onset of sampling, 2DG was administered peripherally (200, 400, or 800 mg/kg BW, iv), and food intake was determined after 2DG injection in gonadectomized males and females in the presence or absence of sex steroids (testosterone or estradiol). To test the ability of the pituitary to produce LH under glucoprivic conditions, LHRH was injected every 30 min for 2.5 h in ovariectomized (OVX) rats 30 min after treatment with 400 mg/kg 2DG. At all peripheral doses of 2DG in females and at the middle and high doses of 2DG in males, mean plasma LH and LH pulse frequency decreased (P < 0.05) in the presence of steroids. However, in the absence of sex steroids, the lowest dose in females and the middle dose in males were not effective. Pituitary function appeared normal, because increases in mean plasma LH in response to the exogenous LHRH occurred in OVX rats treated with the middle dose of 2DG. Food intake significantly (P < 0.05) increased after 2DG injection in all groups except estrogen-treated OVX females at the low and high doses of 2DG. These findings suggest that glucoprivic suppression of LH pulses is potentiated by gonadal steroids in both sexes. Moreover, the hypothalamo- hypophyseal axis of the female rat seems to be more sensitive to the decreased glucose availability induced by 2DG than that of the male.

    DOI: 10.1210/endo.137.4.8625885

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  217. ストレスと生殖をめぐる神経内分泌機構

    束村博子

    ヒューマンサイエンス   Vol. 8   page: 89-97   1996.1

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  218. 生殖機能を制御する脳内メカニズム:GnRH Pulse Generator

    前多敬一郎・大蔵聡・束村博子

    獣医畜産新報   Vol. 49   page: 33-38   1996.1

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  219. Neuroendocrine mechanism mediating fasting-induced suppression of luteinizing hormone secretion in female rats Reviewed

    ACTA NEUROBIOLOGIAE EXPERIMENTALIS   Vol. 56 ( 3 ) page: 787 - 796   1996.1

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    Web of Science

  220. Suppression of luteinizing hormone pulses by restriction of glucose availability is mediated by sensors in the brain stem Reviewed

    Kumiko Murahashi, David C. Bucholtz, Shoji Nagatani, Shinji Tsukahara, Hiroko Tsukamura, Douglas L. Foster, Kei Ichiro Maeda

    Endocrinology   Vol. 137 ( 4 ) page: 1171 - 1176   1996.1

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    The availability of metabolic fuels such as glucose is known to influence reproductive function. Peripheral administration of 2-deoxyglucose (2DG), a competitive inhibitor of glycolysis, inhibits pulsatile LH secretion in the rat and growth-retarded lamb. We hypothesized that such glucoprivic suppression of LH secretion is mediated by the lower brain stem, because studies of both ingestive and reproductive behavior implicate lower brain stem structures, such as the area postrema, as a site that is sensitive to glucose availability. In the present study, the effect of a 2DG infusion, targeted to the fourth ventricle, on pulsatile LH secretion was examined in male rats. The males were castrated or castrated and immediately implanted with testosterone. Blood samples were collected through an indwelling atrial cannula every 6 min for 4 h for LH determination. After the first hour of blood sampling, 2DG (4 or 40 mg/kg) was infused into the fourth ventricle at a flow rate of 0.2 μl/min through a cannula that had been stereotaxically implanted 1 week before sampling. The high dose of 2DG (40 mg/kg), but not the low dose (4 mg/kg), suppressed pulsatile LH secretion and increased food intake in both castrated and testosterone-treated castrated rats. LH secretion and food intake were not affected by the infusion of xylose (40 mg/kg) as an isoosmotic control. The site specificity of the 2DG treatment was confirmed by histological examination after an isovolumetric infusion of dye (0.2 μl/min). These results suggest that glucose availability could influence LH secretion as well as feeding through a central sensor in the lower brain stem and are consistent with the idea that the area postrema might be an important glucosensor involved in the modulation of LH secretion.

    DOI: 10.1210/endo.137.4.8625886

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  221. The LHRH pulse generator: An ultradian pacemaker controlling the hypothalamic hormone secretion.

    "Maeda, K.-I., Tsukamura, H., Ohkura, S. and Yokoyama, A."

    Neuroscience and Biobehavioral Reviews   Vol. 19   page: 427-437   1995.1

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  222. ストレス反応を媒介する神経内分泌機構

    前多敬一郎・長谷祥治・束村博子

    第39回プリマーテス研究会報告     page: 70-73   1995.1

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  223. 繁殖学会島村賞受賞講演論文 - 黄体形成ホルモンのパルス状分泌を制御する中枢機構

    束村博子

    Journal of Reproduction and Development   Vol. 41   page: j103-111   1995.1

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  224. The LHRH pulse generator: A mediobasal hypothalamic location Reviewed

    Kei Ichiro Maeda, Hiroko Tsukamura, Satoshi Ohkura, Shinichi Kawakami, Hiroshi Nagabukuro, Akira Yokoyama

    Neuroscience and Biobehavioral Reviews   Vol. 19 ( 3 ) page: 427 - 437   1995.1

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    The location and mechanism of LHRH pulse generator are discussed based on our series of experiments. Suckling stimulus is a novel stimulus that inhibits LH pulses without any cooperation from ovarian steroids, unlike other stimuli such as stress, photoperiod etc. It is directly involved in suppressing the activity of the LHRH pulse generator. The information from teats suckled by pups or babies is conveyed dorsally to the mediobasal hypothalamus (MBH), where the LHRH pulse generator may be located. Experiments using various types of deafferentation and fetal brain tissue transplantation confirmed that the LHRH pulse generator is located in the MBH and suggested that LHRH pulse generator consists of nonLHRH neurons. Endogenous excitatory amino acid is one of the possible neurotransmitters that regulate LHRH release at the nerve terminal in ME. © 1995.

    DOI: 10.1016/0149-7634(94)00069-D

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  225. Neuroendocrine Mechanisms Regulating Pulsatile Luteinizing Hormone Secretion Reviewed

    Hiroko Tsukamura

    Journal of Reproduction and Development   Vol. 41 ( 6 )   1995

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    Pulsatile LHRH/LH secretion plays a key role in the maintainance of reproductive functions in mammals. The present study suggests that LHRH pulse generator is located in the anterior part of the mediobasal hypothalamus and consists of non-LHRH neurons. Environmental stimuli, such as suckling stimulus and fasting stress profoundly suppresses pulsatile LH secretion. The neural pathway involved in suckling- or fasting-induced suppression of LH pulses was discussed. © 1995, THE SOCIETY FOR REPRODUCTION AND DEVELOPMENT. All rights reserved.

    DOI: 10.1262/jrd.95-416j103

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  226. Estrogen feedback needed at the paraventricular nucleus or A2 to suppress pulsatile luteinizing hormone release in fasting female rats Reviewed

    Shoji Nagatani, Hiroko Tsukamura, Kei Ichiro Maeda

    Endocrinology   Vol. 135 ( 3 ) page: 870 - 875   1994.9

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    The feedback sites of estrogen within the hypothalamus and lower brain stem involved in the suppression of pulsatile LH secretion during 48-h fasting were examined in ovariectomized rats with local estradiol (E2) implants. The animals were ovariectomized and immediately implanted stereotaxically with stainless steel cannula containing crystal E2 diluted 10 times with crystal cholesterol into the medial preoptic area, paraventricular nucleus (PVN), arcuate nucleus (ARC), locus ceruleus, or A1 or A2 region of the brain. Five days later, animals were deprived of food for 48 h, and blood samples were collected every 6 min for 3 h. Animals were immediately refed for 45 h and bled again as described above. Changes in the mean LH concentrations over the 3-h sampling period and the frequency and amplitude of LH pulses were determined by calculating the differences in these parameters between the first and second blood samplings in each animal. Fasting significantly lowered mean LH concentrations in animals implanted with E2 in the A2. The more potent suppression of pulsatile LH release during fasting was found in rats with E2 implants in the PVN: the mean LH concentrations and LH pulse frequency were significantly reduced by fasting in this group. In the animals with E2 implants in the medial preoptic area, ARC, locus ceruleus, or A1, 48-h fasting did not induce any significant changes in LH pulse parameters compared to those in cholesterol-implanted controls. A decrease in LH pulse amplitude was apparent in refed rats as well as fasted animals only when E2 was implanted in the ARC. These results suggest that the feedback action of estrogen at the PVN and/or A2 is required for fasting-induced suppression of pulsatile LH release, as opposed to the so-called negative feedback action of estrogen, which tonically suppresses LH release in nonfasting rats. © 1994 by The Endocrine Society.

    DOI: 10.1210/endo.135.3.8070380

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  227. Corticotropin-releasing hormone mediates suppression of pulsatile luteinizing hormone secretion induced by activation of ±-adrenergic receptors in the paraventricular nucleus in female rats Reviewed

    Hiroko Tsukamura, Shoji Nagatani, Felino R.A. Cagampang, Shinichi Kawakami, Kei Ichiro Maeda

    Endocrinology   Vol. 134 ( 3 ) page: 1460 - 1466   1994.4

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    The present study examined which subtype of adrenergic receptor in the paraventricular nucleus (PVN) has a role in regulating pulsatile LH secretion and whether CRH mediates the effect of norepinephrine (NE) injection into the PVN on pulsatile LH secretion in ovariectomized (OVX) and ovariectomized estradiol (E2)-treated (OVX + E2) rats. All animals were OVX, and some were sc implanted with Silastic capsules containing E2 dissolved in peanut oil. One week after ovariectomy and E2 implantation, guide cannulae for injection of agent and alpha-helical CRF-(9-41) (alpha-hel CRF), an antagonist of CRH, were stereotaxically implanted into the PVN and third ventricle, respectively. Animals were bled for 3 h at 6-min intervals through an atrial cannula immediately after PVN injection of NE or various adrenergic receptor agonists (phenylephrine, an alpha 1-adrenergic receptor agonist; clonidine, an alpha 2-agonist; and isoproterenol, a beta-agonist). Some of the animals were injected with alpha-hel CRF 5 min before NE injection. NE and both alpha-receptor agonists inhibited pulsatile LH secretion throughout the 3-h sampling period in OVX + E2 rats and significantly reduced the mean plasma LH levels and the LH pulse frequency. On the other hand, LH secretion was inhibited transiently for the first 1-2 h by an injection of NE or an alpha 2-receptor agonist into the PVN in OVX rats, resulting in a significant decrease only in mean plasma LH levels in the NE-injected group. Injection of a beta-agonist did not affect pulsatile LH secretion in either OVX or OVX + E2 animals. Intracerebroventricular injection of alpha-hel CRF before PVN injection of NE completely blocked the NE-induced suppression of pulsatile LH secretion in OVX+E2 rats. These results suggest that 1) the noradrenergic system projecting to the PVN suppresses pulsatile LH secretion via the activation of alpha-adrenergic receptors; 2) this inhibition is mediated by CRH release; and 3) estrogen enhances this suppression. © 1994 by The Endocrine Society.

    DOI: 10.1210/endo.134.3.8119187

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  228. Involvement of the catecholaminergic input to the paraventricular nucleus and of corticotropin-releasing hormone in the fasting-induced suppression of luteinizing hormone release in female rats Reviewed

    Kei Ichiro Maeda, Felino R.A. Cagampang, Clive W. Coen, Hiroko Tsukamura

    Endocrinology   Vol. 134 ( 4 ) page: 1718 - 1722   1994.4

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    The roles of the adrenergic projection to the paraventricular nucleus (PVN) and of central CRH in the suppression of pulsatile LH secretion during 48-h fasting were examined in ovariectomized estradiol (E2)-treated rats. The animals were ovariectomized and immediately implanted with Silastic tubing containing E2. One week after ovariectomy and E2 implantation, the animals were implanted stereotaxically with a guide cannula for microinjection into the PVN or intracerebroventricular (icv) injection. One week later, some of the animals were deprived of food for 48 h. The unfasted controls were provided with food ad libitum. At this point, blood samples were collected every 6 min for 3 h. Animals received an injection of 50 μgrams alpha-methyl-p-tyrosine (AMPT), a catecholamine synthesis inhibitor, into the PVN 3 h before the sampling started or an icv injection of 26 nmol alpha-helical CRF-(9-41), a CRH antagonist, after the first hour of blood sampling; control animals were given the vehicle at the equivalent time. The fasted animals injected with AMPT showed a significantly higher mean LH concentration and LH pulse frequency over the 3-h sampling period compared with the vehicle-injected controls. Treatment with AMPT had no significant effect on LH secretion in unfasted animals. The icv injection of alpha-helical CRF-(9-41) reinstated the suppressed LH release in fasted rats, but had no significant effect in unfasted animals. These results suggest that the adrenergic projection to the PVN and central CRH are involved in the suppression of pulsatile LH release during food deprivation. The possibility that fasting activates an ascending adrenergic projection that stimulates CRH release and thus suppresses pulsatile LH secretion is discussed. © 1994 by The Endocrine Society.

    DOI: 10.1210/endo.134.4.8137735

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  229. Differential expression of epidermal growth factor receptor (EGF-R) gene and regulation of EGF-R bioactivity by progesterone and estrogen in the adult mouse uterus Reviewed

    Sanjoy K. Das, Hiroko Tsukamura, Bibhash C. Paria, Glen K. Andrews, Sudhansu K. Dey

    Endocrinology   Vol. 134 ( 2 ) page: 971 - 981   1994.2

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    The present study examined several aspects of epidermal growth factor receptor (EGF-R) in the mouse uterus during the periimplantation period and after ovarian hormone treatment of adult ovariectomized mice. The cell- specific distribution, regulation of expression, and binding kinetics were assessed by immunohistochemistry, Northern blot analysis, and ligand binding assays, respectively. Affinity cross-linking studies ascertained the size of the EGF-R, and its bioactivity was examined by determining EGF-dependent subcellular protein tyrosine kinase activity and receptor autophosphorylation. In the intact uterus and separated cell types, EGF-R was detected in the stroma, deciduum, and myometrium, but not in the luminal or glandular epithelium. Uterine EGF-R mRNA transcript profiles showed some differences between pregnant and ovariectomized mice regardless of steroid hormone treatments. Two major [6.5- and 2.7-kilobase (kb)] and two less abundant (9.6- and 5.0-kb) transcripts were detected in pregnant uterine poly(A)+ RNA. Three additional transcripts (<2.0 kb) were detected in decidual poly(A)+ RNA, and a larger transcript (8.0 kb) was detected in uterine poly(A)+ RNA isolated from ovariectomized mice. Scatchard analysis of EGF binding also revealed apparent differences in binding kinetics between pregnant and ovariectomized mice, although EGF was cross-linked to a 170- kilodalton protein under these conditions. Two classes (K(d), ~0.2 and ~2.0 nM) of binding sites were noted in pregnant mice, whereas a single class (K(d), ~1.0 nM) was found in ovariectomized mice. 17β-Estradiol (E2) caused a rapid transient upregulation of uterine EGF-R mRNA levels and increased the number of EGF-binding sites in ovariectomized mice, as did an injection of progesterone (P4). However, the bioactivity of EGF-R could not be detected in uteri of ovariectomized mice treated with oil or P4. E2 treatment was found to be essential for EGF-R bioactivity. Taken together, the results suggest that in the adult mouse uterus, EGF-R status is influenced by factors other than P4 and E2, the epithelium is not the direct target for the actions of EGF-related growth factors as thought previously, the mitogenic effects of these growth factors on epithelial cells in vivo are perhaps mediated by other uterine cell-types expressing EGF-R, and, lastly, these growth factors are not likely to be functional in the uterus in the absence of estrogen. The present observations are supportive of the concept of paracrine or juxtacrine interactions between EGF-related growth factor ligands of luminal epithelial origin and blastocyst EGF-R in the process of implantation.

    DOI: 10.1210/endo.134.2.7507841

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  230. Uterine epidermal growth factor receptors : Cell-specific expression and regulation of bioactivity by ovarian steroid hormones in adult mice

    Endocrinology   ( 134 ) page: 971-981   1994

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  231. The paraventricular nucleus and corticotrophin-releasing hormone are not critical in suppressing pulsatile LH secretion in ovariectomized lactating rats Reviewed

    H. Tsukamura, S. Ohkura, C. W. Coen, K. I. Maeda

    Journal of Endocrinology   Vol. 137 ( 2 ) page: 291 - 297   1993.5

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    Various types of hypothalamic roof deafferentation (RD) (i.e. large anterior (LARD), large posterior (LPRD), small anterior (SARD) or middle (MRD)), electrolytic lesions of the paraventricular nucleus (PVN) or intracerebroventricular (i.c.v.) injection of α-helical corticotrophin-releasing factor(9-41) (α-helical CRF(9-41)) were performed in ovariectomized lactating rats in order to determine the afferent pathway of the suckling stimulus and whether the PVN and corticotrophin-releasing hormone (CRH) are involved in suppressing pulsatile LH secretion during lactation. Animals were ovariectomized on day 2 of lactation (day 0 = the day of parturition). Deafferentations and electrolytic lesions were made on day 7. On the following day, blood samples were taken via an indwelling atrial cannula every 6 min for 3 h. Pulsatile LH secretion with high frequency and amplitude was present in rats with LARD or LPRD despite the suckling. In rats with MRD, LH pulses with a small amplitude were observed when the cut was on or under the ventral margin of the PVN, but there were few LH pulses when the cut passed through the PVN. Electrolytic lesioning of the PVN, however, did not affect the suppression of pulsatile LH secretion during lactation. In addition, i.c.v. injection of α-helical CRF(9-41) (26.1 nmol/10 μl) into the third ventricle on day 8 of lactation did not reverse the suppression of LH secretion by the suckling stimulus. These results suggest that the pathway associated with this inhibition may be rather diffuse and that the PVN region and CRH are not critical in conveying the inhibitory inputs of the suckling stimulus.

    DOI: 10.1677/joe.0.1370291

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  232. The alpha-2-adrenergic receptors are involved in the suppression of luteinizing hormone release during acute fasting in the ovariectomized estradiol-primed rats. Reviewed

    Neuroendocrinlogy   Vol. 56 ( 5 ) page: 724 - 728   1992.11

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  233. α<inf>2</inf>-adrenergic receptors are involved in the suppression of luteinizing hormone release during acute fasting in the ovariectomized estradiol-primed rats Reviewed

    Felino Ramon A. Cagampang, Satoshi Ohkura, Hiroko Tsukamura, Clive W. Coen, Katsuaki Öta, Kei Ichiro Maeda

    Neuroendocrinology   Vol. 56 ( 5 ) page: 724 - 728   1992.11

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    It has been previously reported that the adrenergic system is involved in the control of feeding behavior and LH release. In the present study, the role of the adrenergic receptors in the suppression of LH release during acute fasting are examined by injecting the α1-antagonist (prazosin), α2antagonists (idazoxan, SKF 86466-A, piperoxan), or β-antagonist (propranolol) into the third ventricle of unfasted and 48 h fasted ovariectomized estradiol-treated rats. Blood samples were collected every 6 min for 3 h and the drugs were administered after the first hour of the sampling period. Prazosin caused a significant suppression of LH release in the unfasted animals while idazoxan and propranolol had no significant effects. In contrast, all α2antagonists blocked the inhibitory effect of fasting on LH release and significantly reinstated the suppressed LH release while prazosin and propranolol had no significant effects. We conclude from these results that the suppression of LH release during acute fasting is mediated by α2-adrenergic receptors but not α1- or β-adrener- gic receptors. © 1992 S. Karger AG, Basel.

    DOI: 10.1159/000126299

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  234. Effects of transplants of fetal mediobasal hypothalamus on luteinizing hormone pulses impaired by hypothalamic deafferentation in adult ovariectomized rats Reviewed

    Satoshi Ohkura, Hiroko Tsukamura, Kei Ichiro Maeda

    Neuroendocrinology   Vol. 55 ( 4 ) page: 422 - 426   1992.4

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    Pulsatile luteinizing hormone (LH) secretion is impaired after posterior anterior-hypothalamic deafferentation (PAD), which separates the anterior part of the arcuate nucleus from the mediobasal hypothalamus (MBH). In the present study, we examined whether transplants of fetal brain tissue could prevent the effects of PAD. The brain tissue containing the MBH or the cerebral cortex taken from the fetal brain was transplanted into the third ventricle of ovariectomized rats. Four weeks after the brain transplantation, animals with or without the brain transplantation were subjected to PAD. One week after PAD, blood samples were collected every 6 min for 3 h through an indwelling atrial cannula. Rats bearing PAD without transplantation showed irregular pulsatile fluctuation of plasma LH, whereas LH pulses were maintained in rats bearing transplantation of the fetal MBH tissue. In rats which had been transplanted with the cerebral cortex, LH pulses were less apparent after PAD than in the MBH-transplanted or sham-deafferentated animals. No cell bodies of LH-releasing hormone (LHRH) neurons were found immu- nohistochemically in the MBH grafts. These results suggest that the graft containing the fetal MBH tissue maintains regular LH pulses after PAD and that the LHRH pulse generator may consist, at least in part, of a group of neurons in the MBH other than LHRH-producing neurons. © 1992 S. Karger AG, Basel.

    DOI: 10.1159/000126153

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  235. 生殖機能の環境による調節-その神経内分泌学的機序-

    日本畜産学会報     page: 63   1992

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  236. TAP-144の徐放性製剤(TAP-144SR)の単回投与が雌性ラットの性周期および血中性腺刺激ホルモン濃度に及ぼす影響

    薬理と治療     page: 20   1992

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  237. The Endogenous Opioids Do Not Mediate the Suckling-Induced Suppression of LH Secretion in Lactating Rats Reviewed

    Hiroko Tsukamura, Satoshi Ohkura, Kei ichiro Maeda

    Journal of Reproduction and Development   Vol. 38 ( 2 ) page: 159 - 164   1992

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    The effect of intravenous injection of naloxone on the suppression of LH secretion during lactation was examined in intact, ovariectonnized, and ovariectomized steroid-primed lactating rats at early and late lactation. The day of parturition was designated day 0. The litter size was adjusted to 8 on day 1, and ovariectomy was performed on day 2. Progesterone alone or progesterone and estradiol in silicone capsules were implanted subcutaneously immediately after the ovariectomy. Blood samples were collected every 6 min for 3 h on day 8 and 16 in intact and ovariectomized rats and on day 16 in ovariectomized steroid-primed rats. Naloxone (total amount=1.2 mg) was injected intravenously via the sampling catheter every 6 min for 2 h after the first hour of the sampling period. Intravenous injection of naloxone had no significant effect on plasma concentrations of LH on day 8 in intact or ovariectomized lactating rats. On day 16, naloxone treatment increased the plasma level of LH in intact lactating rats but not in ovariectomized or ovariectomized steroid-primed lactating rats. The present study clearly indicates that the endogenous opioid peptides do not mediate the suppression of the LH release by suckling stimulus, since intravenous injection of naloxone did not increase the LH secretion at early lactation when the suckling stimulus is the dominant factor suppressing LH release. © 1992, THE SOCIETY FOR REPRODUCTION AND DEVELOPMENT. All rights reserved.

    DOI: 10.1262/jrd.38.159

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  238. Effects of Various Types of Hypothalamic Deafferentation on Luteinizing Hormone Pulses in Ovariectomized Rats Reviewed

    Satoshi Ohkura, Hiroko Tsukamura, Kei‐ichiro ‐i Maeda

    Journal of Neuroendocrinology   Vol. 3 ( 5 ) page: 503 - 508   1991.10

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    The pulsatile luteinizing hormone (LH) secretion in chronically ovariectomized rats bearing various types of hypothalamic deafferentation was examined. Ovariectomized rats were subjected to complete, anterolateral or anterior hypothalamic deafferentation and bled every 6 min for 3 h through an indwelling atrial cannula 5 days after the brain surgery. Another group of ovariectomized animals was subjected to posterior‐anterior hypothalamic deafferentation (PAD), which cut off the anterior part of the arcuate nucleus from the mediobasal hypothalamus, and bled 1, 3 or 5 weeks after the deafferentation. Coronal sections of the brain were immunostained with anti‐LH‐releasing hormone (LHRH) serum. The pulsatile LH secretion was observed in rats bearing anterior, anterolateral or complete hypothalamic deafferentation and these types of deafferentation did not affect the frequency of LH pulses. The mean LH level during the 3‐h sampling period and the amplitude of LH pulses decreased as the incision extended postero‐laterally. Rats bearing PAD showed an irregular fluctuating pattern in plasma LH concentration 1 week after PAD. Parameters of LH pulses were restored with time after PAD. This suggests that the system generating LHRH pulses severed by PAD had been reorganized. LHRH‐immunopositive neuronal fibres were found in the external layer of the median eminence in the rats bearing any type of deafferentation. The present results suggest that the frequency of LH pulses could be controlled by the LHRH pulse generator, which consists of non‐LHRH neurons and is located in the mediobasal hypothalamus. Copyright © 1991, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1365-2826.1991.tb00310.x

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  239. Suppression of ovarian activity during the breeding season in suckling Japanese monkey (Macaca fuscata) Reviewed

    K. I. Maeda, H. Tsukamura, S. Ohkura, T. Kanaizuka, J. Suzuki

    Journal of Reproduction and Fertility   Vol. 92 ( 2 ) page: 371 - 375   1991.7

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    The menstrual cycle was examined in Japanese monkeys, short-day breeders, with or without nursing babies during the breeding season by determining the change in the plasma concentration of progesterone. Blood samples were obtained weekly from suckling and nonsuckling mothers for 6 months from September to February. Plasma concentrations of progesterone in suckling mothers did not show any apparent fluctuation and remained low throughout the study, while irregular menstruation was observed. In nonsuckling mothers, cyclic changes in plasma progesterone concentration accompanied by regular menstruation occurred from October. Annual birth rates were lower in monkeys housed in individual cages (17.6%) than in free-ranging monkeys in Miyajima colony, near Hiroshima in Japan (37.5%). These results indicate that the suckling stimulus for females with young born in spring is potent enough to suppress ovarian activity during the autumn breeding season.

    DOI: 10.1530/jrf.0.0920371

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  240. Involvement of ovarian steroids and endogenous opioids in the fasting-induced suppression of pulsatile LH release in ovariectomized rats Reviewed

    F. R.A. Cagampang, K. I. Maeda, H. Tsukamura, S. Phkura, K. Ota

    Journal of Endocrinology   Vol. 129 ( 3 ) page: 321 - 328   1991.6

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    The participation of the ovarian steroids and opioid peptides in the suppression of pulsatile LH release during acute fasting was examined in rats. Ovariectomized rats bearing silicone elastomer implants of oestradiol and/or progesterone were fasted for 48 h and subsequently blood samples were taken every 6 min for 3 h. Pulsatile LH release was suppressed after 48 h of fasting in the ovariectomized rats implanted with oestradiol but not in the oil-implanted controls. This suppression was enhanced after the administration of progesterone together with oestradiol. In a second experiment, ovariectomized rats bearing implants of oestradiol or oil were fasted for 48 h and injected s.c. (2.5 mg/kg body weight) with an opioid antagonist, naloxone hydrochloride, immediately before blood sampling. In the fasted oestradiol-treated ovariectomized rats, naloxone was able to prevent the suppression of pulsatile LH release. In the absence of oestradiol, however, naloxone was without effect on LH release in either the fasted or unfasted animals. These experiments indicate that the suppression of pulsatile LH release after 48 h of fasting is dependent upon oestradiol and that endogenous opioids are involved in the suppression.

    DOI: 10.1677/joe.0.1290321

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  241. Epidermal growth factor-specific protein tyrosine phosphorylation in preimplantation embryo development Reviewed

    B. C. Paria, H. Tsukamura, S. K. Dey

    Biology of Reproduction   Vol. 45 ( 5 ) page: 711 - 718   1991

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    DOI: 10.1095/biolreprod45.5.711

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  242. The suppressing effect of the sucking stimulus on the pulsatile luteinzing hormone release is not mediated by prolactin in the rat at mid-lactation. Reviewed

    TSUKAMURA Hiroko, MAEDA Kei-Ichiro, OHKURA Satoshi, UCHIDA Emi, YOKOYAMA Akira

    Journal of Reproduction and Development   Vol. 37 ( 1 ) page: 59 - 63   1991

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    The effect of the reduction of prolactin (PRL) release by the bromocriptine (CB-154) treatment on suppression of luteinizing hormone (LH) pulses by the suckling stimulus was examined in ovariectomized lactating rats at mid-lactation. Litter size was adjusted to 8 on day 1 (day 0=the day of parturition). Postpartum rats deprived of their pups on day 2 served as non-lactating controls. All rats were ovariectomized on day 2. CB-154 (0.6 mg/day) or saline was injected daily into both lactating and non-lactating rats from day 2. Ovine PRL (0.3 mg/day) was infused with a mini-osmotic pump into the half of the animals treated with CB-154. Litters were rotated every day among a CB-154 treated mother, 2 intact mothers and a saline-injected mother to ensure the similar strength of the suckling stimulus. Blood samples were taken at 6-min intervals for 3 hr on day 7 or 8. Pulsatile LH secretion was strongly suppressed in all lactating rats in spite of the treatment of CB-154. Frequent LH pulses were observed in all non-lactating animals, suggesting that CB-154 or ovine PRL did not directly affect LH secretion at the doses employed. These results suggest that PRL does not mediate the suppressing effect of the suckling stimulus on pulsatile LH secretion in rats at mid-lactation.

    DOI: 10.1262/jrd1977.37.59

  243. Effect of Hypothalamic Deafferentation on the Pulsatile Secretion of Luteinizing Hormone in Ovariectomized Lactating Rats Reviewed

    Hiroko Tsukamura, Kei‐ichiro ‐i Maeda, Satoshi Ohkura, Akira Yokoyama

    Journal of Neuroendocrinology   Vol. 2 ( 1 ) page: 59 - 63   1990.2

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    The pulsatile luteinizing hormone (LH) secretion in ovariectomized lactating rats bearing complete (CD), anterior (AD), anterolateral (ALD), posterior (PD), or roof (RD) deafferentation of the hypothalamus was determined. All lactating rats were ovariectomized on Day 2 of lactation (Day 0, day of parturition). The deafferentation of nerve fibres to the mediobasal hypothalamus was performed on Day 6 or 7 of lactation. Twenty‐four h after the surgery, blood samples were taken through the indwelling atrial catheter every 6 min for 3 h. Plasma concentrations of LH and prolactin (PRL) were measured by radioimmunoassay. The loss of LH pulses associated with lactation was still apparent following AD, PD and sham‐deafferentation (SD); pulsatile LH secretion was, however, present in rats with CD, ALD and RD despite continued suckling. The only significant difference in plasma PRL concentrations among the various groups was a reduction in the PRL level in rats with RD in comparison to those with SD. We conclude that the neural signal responsible for the inhibition of pulsatile LH release by suckling is conveyed through the dorsal part of the hypothalamus and PRL does not mediate the suppression of LH pulses in mid‐lactation. Copyright © 1990, Wiley Blackwell. All rights reserved

    DOI: 10.1111/j.1365-2826.1990.tb00393.x

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  244. TAP-144の徐放性製(TAP-144-SR)の性腺機能抑制効果に関する検討

    薬理と治療     page: 18   1990

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  245. Prolactin does not Mediate the Suppressive Effect of the Suckling Stimulus on Luteinizing Hormone Secretion in Ovariectomized Lactating Rats Reviewed

    Kei Ichiro Maeda, Emi Uchida, Hiroko Tsukamura, Naganari Ohkura, Satoshi Ohkura, Akira Yokoyama

    Endocrinologia Japonica   Vol. 37 ( 3 ) page: 405 - 411   1990

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    The plasma LH concentration in ovariectomized lactating rats is low for 14 days postpartum, while the prolactin concentration is high during this period. We examined the effect of the inhibition of increased prolactin secretion with bromocriptine (CB-154) on the LH secretion in lactating rats ovariectomized on day 2 (day 0=day of parturition). Blood samples were collected through an indwelling atrial cannula every day. LH levels were kept low until day 9 in lactating rats injected daily with CB-154 (0.6 mg/day, s. c). The duration of the period during which LH secretion was suppressed was shorter in lactating rats treated with CB-154 than in saline-injected controls. The replacement with ovine prolactin by means of a mini-osmotic pump (0.3 mg/day, s. c.) in CB-154-treated lactating rats restored the duration of LH suppression. In rats deprived of their pups on day 2, the LH concentration rose immediately after removal of the pups and the LH level was not significantly different between rats treated with CB-154, ovine prolactin and saline, indicating that neither the CB-154 treatment nor the high level of prolactin alone has any effect on LH secretion in rats deprived of their pups. The present results clearly demonstrate that prolactin does not mediate the suppressing effect of the suckling stimulus on LH secretion in early lactation and support our theory that the suckling stimulus controls the LH and prolactin secretion independently at the hypothalamic level. © 1990, The Japan Endocrine Society. All rights reserved.

    DOI: 10.1507/endocrj1954.37.405

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  246. ラットにおける無拘束、無麻酔下採血のためのカニューレ装着法の実際

    アニテックス     page: 1   1989

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  247. Changes in the pulsatile secretion of LH after the removal of and subsequent resuckling by pups in ovariectomized lactating rats Reviewed

    K. I. Maeda, H. Tsukamura, E. Uchida, N. Ohkura, S. Ohkura, A. Yokoyama

    Journal of Endocrinology   Vol. 121 ( 2 ) page: 277 - 283   1989

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    Changes in the pulsatile secretion of LH after removal of pups and subsequent resuckling were examined in ovariectomized lactating rats, and the change after removal of pups was compared with that after the removal of ovaries in cyclic female rats. The day of parturition was designated day 0 of lactation. All lactating rats were ovariectomized on day 2 of lactation. They were deprived of their pups for 6, 12, 18, 24, or 45 h before blood sampling on day 8 of lactation, or were suckling by their pups for 1, 4, 7 or 12 h before blood collection after separation from pups for 24 h. Cyclic female rats were ovariectomized on the day of dioestrus and blood samples were taken 12, 18, 24 or 48 h or 6 days after ovariectomy. Typical LH pulses appeared in some animals from 12 h after the removal of pups. The mean LH level and the frequency and amplitude of LH pulses gradually increased after removal of pups, until after 45 h of separation the frequency reached the high level observed 6 days after ovariectomy in cyclic rats. The subsequent resuckling by pups after a 24-h separation decreased these three parameters of LH pulses rapidly. In contrast, the frequency of LH pulses was unchanged after ovariectomy in cyclic rats, although the mean LH level and the amplitude of LH pulses increased. These results suggest that the suckling stimulus suppresses pulsatile LH secretion in a different manner from that of ovarian steroids.

    DOI: 10.1677/joe.0.1210277

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  248. Effect of the suckling stimulus on daily LH surges induced by chronic oestrogen treatment in ovariectomized lactating rats Reviewed

    H. Tsukamura, K. I. Maeda, A. Yokoyama

    Journal of Endocrinology   Vol. 118 ( 2 ) page: 311 - 316   1988

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    Effects of the suckling stimulus on the daily LH surge induced by chronic oestrogen treatment were examined in ovariectomized lactating rats. Wistar-Imamichi strain rats were kept under 14 h light:10 h darkness (lights on at 05.00 h). Litter size was adjusted to eight on day 1 (day 0 = day of parturition) and ovariectomy performed on day 2. Lactating rats deprived of their litters on day 0 served as nonlactating controls. Silicone elastomer tubing filled with oestradiol was implanted on day 6 or 15. Blood samples were collected through an indwelling cannula at 10.00 and 17.00 h on each day after implantation to detect daily LH surges. Daily LH surges occurred in the late afternoon in both lactating and non-lactating rats implanted with oestradiol on day 6 or 15. The amplitude of daily LH surges in lactating rats implanted on day 6 declined much more rapidly than in non-lactating rats implanted on day 6, but no significant difference was found in the profile of the LH surge between lactating and non-lactating rats implanted on day 15. Pituitary LH contents just before the daily LH surge (12.00-12.30 h) 4 days after implantation in lactating rats implanted with oestradiol on day 6 were significantly less than those in non-lactating rats implanted with oestradiol on day 6 or 15 and in lactating rats implanted on day 15. These results suggest that the mechanisms responsible for the oestradiol-induced LH surge were not impaired by the suckling stimulus, and that a rapid decline of the amplitude of LH surges observed in mid-lactation could be ascribed to the small amount of LH stored in the pituitary.

    DOI: 10.1677/joe.0.1180311

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  249. Effects of the electrical stimulation of the mammary nerve on oxytocin and luteinizing hormone secretion in anesthetized rats. Reviewed

    MAEDA Kei-ichiro, OHKURA Naganari, UCHIDA Emi, TSUKAMURA Hiroko, YOKOYAMA Akira

    Journal of Reproduction and Development   Vol. 34 ( 3 ) page: 153 - 158   1988

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    Effects of the electrical stimulation of the mammary nerve on oxytocin (OT) and luteinizing hormone (LH) secretion in anesthetized lactating rats were examined. The electrical stimulation of the mammary nerve as well as the saphenous and the median nerve increased the plasma OT concentration in both lactating and cycling rats under urethane anesthesia. All groups of rats stimulated with these nerves showed a very similar pattern of OT release which was different from those observed in lactating rats suckled by pups. The electrical stimulation of the mammary nerve decreased the plasma LH concentration in ovariectomized lactating rats that had been deprived of their pups for 24 hr compared with the concentration obtained after the stimulation of the saphenous nerve. The possibility still remains that the electrical stimulation of the mammary nerve could be used as a substitute for the suckling stimulus.

    DOI: 10.1262/jrd1977.34.153

  250. 泌乳中排卵しないのはなぜか?

    生物物理     page: 27   1987

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  251. Suppression of Luteinizing Hormone Secretion is Removed at Late Lactation in Ovariectomized Lactating Rats Reviewed

    Kei Ichiro Maeda, Hiroko Tsukamura, Akira Yokoyama

    Endocrinologia Japonica   Vol. 34 ( 5 ) page: 709 - 716   1987

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    The effect of the suckling stimulus on pulsatile luteinizing hormone (LH) secretion in mid- and late lactation (days 10 and 20 of lactation) in rats was examined. Pulsatile LH secretion was strongly suppressed on either day 10 or 20 of lactation in intact rats in which the baselines of LH secretion were kept very low. In ovariectomized rats the baseline was kept as low as was observed in intact rats on day 10 of lactation, and pulsatile LH secretion was observed in 3 out of 6 rats. On day 20 the baseline secretion increased and pulsatile LH secretion was observed in 5 out of 6 rats, and the baseline for each rat showed various levels. These results clearly indicate that the pulsatile LH secretion was strongly suppressed until ovulation occurred on day 18–23 of lactation in intact rats and suggest that suppression of pulsatile LH secretion by the suckling stimulus at the hypothalamo-pituitary level is removed in late lactation and the time of the removal varies from animal to animal. © 1987, The Japan Endocrine Society. All rights reserved.

    DOI: 10.1507/endocrj1954.34.709

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  1. 死してこそ成し遂げる : 食料問題を追い続けた獣医学研究者が語り、遺し、託したこと

    前多, 敬一郎, 束村, 博子( Role: Sole author)

    平凡社  2020.3  ( ISBN:9784582838381

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    Total pages:507p   Language:Japanese

    CiNii Books

  2. The GnRH Neuron and its Control

    Tsukamura H, Maeda KI, Uenoyama Y. ( Role: Sole author)

    Wiley  2018 

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    Language:English Book type:Scholarly book

  3. 新たな中枢性繁殖制御剤のシーズ:KNDyニューロン

    前多敬一郎・大石真也・束村博子・上野山賀久・大蔵聡・松田二子( Role: Joint author)

    MPアグロジャーナル  2014 

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  4. 繁殖生物学「中枢神経系の性分化」

    奥田潔・宮野隆・高坂哲也・大蔵聡・代田眞理子・田中知己・岡村裕昭・河野友宏・尾畑やよい・金井克晃・束村博子・渡辺元・服部眞彰・田中智・今川和彦・高橋祐司・細井美彦・長嶋比呂志・若山照彦( Role: Joint author)

    インターズー  2013.9 

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  5. Kisspeptin and GnRH Pulse Generation

    Okamura H, Tsukamura H, Ohkura S, Uenoyama Y, Wakabayashi Y, Maeda KI. ( Role: Joint author)

    Adv Exp Med Biol.   2013 

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  6. 繁殖障害の根本治療に向けての新たな方法論:KNDyニューロンの応用

    前多敬一郎・大蔵聡・松田二子・難波陽介・若林嘉昭・岡村裕昭・井上直子・上野山賀久・束村博子( Role: Joint author)

    家畜診療  2012 

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  7. キスペプチンと生殖腺刺激ホルモン放出ホルモン(GnRH)分泌

    井上直子・束村博子・前多敬一郎( Role: Joint author)

    月刊 臨床神経科学  2012 

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  8. ストレスが繁殖に与える影響〜内分泌学的影響と知見〜

    前多敬一郎・束村博子・上野山賀久 ( Role: Joint author)

    臨床獣医  2012 

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  9. 生理活性ペプチド・機能性ペプチド−研究の最先端−キスペプチンによる繁殖機能制御機構

    上野山賀久・大蔵聡・井上直子・前多敬一郎・束村博子( Role: Joint author)

    臨床化学   2011 

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  10. 卵胞発育と成熟(1) 卵胞発育の中枢制御機構

    井上直子・上野山賀久・大蔵聡・束村博子・前多敬一郎( Role: Joint author)

    2011 

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  11. キスペプチン/メタスチン−繁殖を制御する新規神経ペプチド

    大蔵聡・上野山賀久・冨川順子・井上直子・束村博子・前多敬一郎( Role: Joint author)

    日本産業動物獣医師会雑誌  2010 

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  12. Neurobiological mechanisms underlying GnRH pulse generation by the hypothalamus

    Maeda, K.-I., Ohkura, S., Uenoyama, Y., Wakabayashi, Y., Oka, Y., Tsukamura, H. and Okamura, H. ( Role: Joint author)

    Brain Research   2010 

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  13. Sexual differentiation of kisspeptin neurons responsible for sex difference in gonadotropin release in rats

    Tsukamura, H., Homma, T., Tomikawa, J., Uenoyama, Y. and Maeda, K.-I. ( Role: Joint author)

    Annals of the New York Academy of Sciences  2010 

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  14. 生周期とニューロペプチド(1) キスペプチン

    本間玲実・冨川順子・上野山賀久・前多敬一郎・束村博子( Role: Sole author)

    2010 

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  15. 生殖機能調節の新しい視点 3 思春期/性成熟のタイミングを決定するキスペプチン/メタスチン

    上野山賀久・大蔵聡・束村博子・前多敬一郎( Role: Joint author)

    産科と婦人科  2010 

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  16. Kisspeptin/metastinと生殖機能制御

    冨川順子・上野山賀久・束村博子・前多敬一郎( Role: Joint author)

    糖尿病・代謝・内分泌2010  2010 

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  17. バイオテクノロジーと家畜”「ヒトと動物の関係学」第2巻「家畜の文化」

    前多敬一郎・束村博子( Role: Joint author)

    岩波書店  2009.2 

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  18. 家畜の文化

    秋篠宮, 文仁, 林, 良博, 石毛, 直道, 神谷, 信明, 荒俣, 宏, 小林, 章夫, 小長谷, 有紀, 高井, 康弘, 石川, 菜央, 楠瀬, 良, 葛野, 浩昭, Stewart, Henry, 波多野, 鷹, 菅, 豊, 家森, 幸男, 山田, 章雄, 前多, 敬一郎, 束村, 博子, 松原, 豊彦, 佐藤, 衆介( Role: Sole author)

    岩波書店  2009.2  ( ISBN:9784000271080

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    Total pages:280p   Language:Japanese

    CiNii Books

  19. Physiological role of metastin/kisspeptin in regulating gonadotropin-releasing hormone (GnRH) secretion in female rats

    Ohkura, S., Uenoyama, Y., Yamada, S., Homma, T., Takase,K., Inoue, N., Maeda, K.-I. and Tsukamura, H.( Role: Joint author)

    Peptides  2009.1 

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  20. エストロゲンと視床下部―フィードバック機構の鍵を握るメタスチン/キスペプチンニューロンの役割

    束村博子・前多敬一郎( Role: Joint author)

    産科と婦人科  2009 

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  21. 名古屋発!改革ムーブメント①~シリーズ・女性研究者を活かす 発展型女性研究者支援名大モデル①~

    榊原千鶴・束村博子( Role: Joint author)

    文部科学教育通信(大学広報発信通信) ジ アース教育新社  2009 

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  22. 生殖機能調節の新しい視点 3 思春期/性成熟のタイミングを決定するキスペプチン/メタスチン

    上野山賀久、大蔵聡、束村博子、前多敬一郎( Role: Joint author)

    産科と婦人科  2009 

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  23. キスペプチン(メタスチン)による繁殖機能制御とその応用

    上野山賀久・束村博子・前多敬一郎( Role: Joint author)

    医学のあゆみ  2008.12 

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  24. 視床下部-下垂体-性腺軸のマスターレギュレーターとしてのメタスチン(キスペプチン)

    束村博子・上野山賀久・山田俊児・冨川順子・井上直子・大蔵聡・前多敬一郎( Role: Joint author)

    ホルモンと臨床  2008.8 

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  25. メタスチン/キスペプチンー種を超えて生殖を司る神経ペプチドGnRHの上位にあって性腺刺激ホルモン分泌をコントロールする

    束村博子、上野山賀久、大蔵聡、前多敬一郎( Role: Joint author)

    化学と生物  2008.4 

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  26. 性差とは何か?―ジェンダー研究と生物学の対話―

    束村博子( Role: Sole author)

    日本学術協力財団  2008.1 

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  27. 性差とは何か : ジェンダー研究と生物学の対話

    日本学術協力財団, 金澤, 一郎, 原, ひろ子, 上野, 千鶴子, 辻村, みよ子, 渡辺, 美代子, 中道, 仁美, 桜井, 万里子, 姫岡, とし子, 竹村, 和子, 大沢, 真理, 江原, 由美子, 長谷川, 真理子, 束村, 博子, 田中, 冨久子, 黒田, 公美, 大内, 尉義, 加賀谷, 淳子, 小川, 眞里子, 松田, 昌子, 井谷, 惠子( Role: Sole author)

    日本学術協力財団  2008.1  ( ISBN:9784939091230

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    Total pages:311p   Language:Japanese

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  28. 生殖を司る神経ペプチド, メタスチン(キスペプチン)

    束村博子・前多敬一郎( Role: Joint author)

    成長発達  2008 

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  29. メタスチン(キスペプチン)研究で生殖の謎を解くー応用の可能性も含めてー

    束村博子( Role: Sole author)

    生物科学  2008 

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  30. Kisspeptin/metastin: A key molecule controlling two modes of gonadotropin-releasing hormone/luteinizing hormone release in female rats.

    Uenoyama Y., Tsukamura H., and Maeda K.-I. ( Role: Joint author)

    Journal of Neuroendocrinology  2008 

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  31. メタスチン(キスペプチン):新しい繁殖制御の可能性を秘めた神経ペプチド

    前多敬一郎、上野山賀久、束村博子( Role: Joint author)

    臨床獣医  2007.11 

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  32. 生理的GnRH放出因子,メタスチン(キスペプチン)の基礎と応用

    前多敬一郎・束村博子( Role: Joint author)

    全国農業共済協会  2007.10 

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  33. metastin(キスペプチンkisspeptin)とGnRH分泌

    前多敬一郎、束村博子( Role: Joint author)

    日本比較内分泌学会  2007.8 

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  34. 繁殖メカニズムの中核ペプチド、メタスチン(キスペプチン)をめぐる新しい性腺刺激剤の可能性(その1)―家畜人工授精―

    前多敬一郎、上野山賀久、大蔵聡、束村博子( Role: Joint author)

    日本家畜人工授精師協会  2007.7 

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  35. 生殖機能の神経内分泌メカニズムー内分泌と生命現象~シリーズ21世紀の動物科学~―

    大蔵聡、木下美香、上野山賀久、束村博子、前多敬一郎( Role: Joint author)

    培風館  2007.7 

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  36. ―セックスとジェンダー、そして男女共同参画―「ジェンダー法・政策研究叢書」

    束村博子( Role: Joint author)

    東北大学出版会  2007 

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  37. メタスチン -特集 中枢内分泌の最新知見とその異常-

    上野山賀久、束村博子、前多敬一郎( Role: Joint author)

    産科と婦人科  2007 

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  38. 繁殖機能を制御するエネルギーセンサーとその応用の可能性 ―特集 家畜における栄養と繁殖機能についての最前線-

    岩田衣世、束村博子、前多敬一郎( Role: Joint author)

    2007 

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  39. Metastin/kisspeptin and control of estrous cycle in rats

    Maeda, K., Adachi, S., Inoue, K., Ohkura, S. and Tsukamura, H.( Role: Joint author)

    Reviews in Endocrine and Metabolic Disorders  2007 

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  40. メタスチン(キスペプチン):生殖機能を制御する神経ペプチドー新しいGPCRリガンド研究の現状と展望ー

    前多敬一郎、束村博子( Role: Joint author)

    ホルモンと臨床  2007 

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  41. ―大学における「男女共同参画」推進のための提言-名古屋大学における男女共同参画の取り組みから見えるもの―「ジェンダー法・政策研究叢書」

    束村博子( Role: Joint author)

    東北大学出版会  2007 

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  42. 絶食および低栄養ストレスによる生殖機能抑制の脳内メカニズムの解明

    束村, 博子( Role: Sole author)

    [出版者不明]  2006.3 

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  43. Neuroendocrine mechanism mediating energetic regulation of gonadotropin release in female rats

    Tsukamura, H., Kinoshita, M., and Maeda, K.-I.( Role: Joint author)

    Animal Science Journal  2006 

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  44. 女と男はどうちがうのか?―生物学的視点からのアプローチー

    束村博子( Role: Sole author)

    学術の動向  2006 

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  45. メタスチン:生殖機能を制御する中心的ペプチド 特集「GPCR研究の最前線」

    束村博子、木下美香、足立幸香、井上金治、前多敬一郎( Role: Joint author)

    内分泌/糖尿病科  2006 

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  46. The Impact of Stress on Reproduction: Are Glucocorticoids Inhibitory or Protective to Gonadotropin Secretion?

    Maeda, K.-I., and Tsukamura, H.( Role: Joint author)

    Endocrinology  2006 

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  47. テキスト母性看護I(改訂版)

    後藤節子編( Role: Joint author)

    名古屋大学出版会  2005 

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  48. 脳の性分化

    新井康正・山内編( Role: Joint author)

    裳華房  2005 

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  49. ジェンダーを科学する

    松本伊瑳子、金井篤子(編)( Role: Joint author)

    ナカニシヤ出版  2004 

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  50. 低栄養ストレスと生殖機能

    前多敬一郎・束村博子( Role: Joint author)

    実験動物技術  2004 

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  51. 絶食ストレスによる性腺機能抑制におけるエストロジェンの脳内作用機序の解明

    束村, 博子( Role: Sole author)

    [出版者不明]  2003.3 

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    CiNii Books

  52. ブルーバックス「生命をあやつるホルモン」

    日本比較内分泌学会編( Role: Joint author)

    講談社  2003 

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  53. 泌乳期における生殖内分泌機能の栄養修飾.

    束村博子( Role: Sole author)

    栄養生理研究年報  2001.10 

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  54. 絶食ストレスによる性腺機能抑制におけるエストロジェンフィードバックの脳内機構

    束村, 博子( Role: Sole author)

    [出版者不明]  2001.3 

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  55. 畜産用語辞典

    日本畜産学会編、養賢堂  2001 

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  56. Novel estrogen feedback associated with fasting-induced suppression of luteinizing hormone secretion in female rats.

    Neuroplasticity Development & Steroid Hormone Action, CRC Press  2001 

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  57. Non-metabolic and metabolic factors causing the lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother.

    Progress in Brain Research, Elsevier  2001 

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  58. Progress in Brain Research

    "Tsukamura. H. and Maeda, K.-I.( EDITOR:Russell, J.A., Douglas, A.J., Windle, R.J. and Ingram, C.D.)"( Role: Joint author)

    Elsevier  2001 

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    Non-metabolic and metabolic factors causing the lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother.

  59. Neuroplasticity Development & Steroid Hormone Action.

    "60. Tsukamura, H., Estacio, M.A.C., Reyes, B.A.S. and Maeda, K.-I.( EDITOR:Handa, R.J., Hayashi, S., Terasawa, E. and Kawata, M)"( Role: Joint author)

    Boca Raton  2001 

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    Novel estrogen feedback associated with fasting-induced suppression of luteinizing hormone secretion in female rats.

  60. Endocrinology.

    Handbook of Experimental Animals, The Laboratory rat  2000 

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  61. Physiology of Reproduction.

    Handbook of Experimental Animals, The Laboratory rat  2000 

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  62. Handbook of Experimental Animals Series: The laboratory rat

    "Ohkura, S., Maeda, K.-I. and Tsukamura, H.( EDITOR:Krinke, G.J. et al.)"( Role: Joint author)

    Academic Press  2000 

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    Endocrinology

  63. からだの中からストレスをみる

    束村博子・前多敬一郎( 編:日本比較内分泌学会)( Role: Joint author)

    学会出版センター  2000 

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    ストレスと生殖

  64. 絶食ストレスによる性腺機能抑制の脳内メカニズム

    束村, 博子( Role: Sole author)

    [出版者不明]  1998.3 

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  65. Positive feedback mechanism of estrogen in the arcuate nucleus.

    Reproductive Biology Update  1998 

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  66. Links between nutrition and reproduction : signals, sensors and pathways controlling GnRH secretion.

    Nutrition and Reproduction  1998 

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  67. Neuroendocrine aspects of nutritional regulation of the gonadal axis : Concepts derived from the rat model.

    Reproductive Biology Update  1998 

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  68. 周排卵期の神経内分泌

    束村博子( Role: Sole author)

    1998 

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  69. ストレス反応における性ステロイドフィードバックメカニズム、特集「脳とステロイドホルモン」

    前多敬一郎・束村博子( Role: Joint author)

    神経研究の進歩  1998 

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  70. 脳と生殖-GnRH神経系の進化と適応

    束村博子( 編:GnRH研究会)( Role: Joint author)

    学会出版センター  1998 

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    1. GnRH序論

  71. Reproductive Biology Update: Novel Tools for Assessment of Reproductive Toxicity

    "Tsukahara, S., Tsukamura, H. and Maeda, K.-I.( EDITOR:Miyamoto, H. and Manabe, N.)"( Role: Joint author)

    Shoukadoh Booksellers Co.  1998 

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    Positive feedback mechanism of estrogen in the arcuate nucleus

  72. Reproductive Biology Update: Novel Tools for Assessment of Reproductive Toxicity

    "Maeda, K.-I., Cagampang, F.R.A., nagatani, S., Estacio, M.A., Murahashi, K., Moriyama, R., Kuroda, A., Tsukahara, S., Bucholtz, D.C., Thompson, R., Foster, D.L. and Tsukamura, H.( EDITOR:Miyamoto, H. and Manabe, N.)"( Role: Joint author)

    Shoukadoh Booksellers Co.  1998 

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    Neuroendocrine aspects of nutritional regulation of the gonadal axis: concepts derived from the rat model

  73. Nutrition and Reproduction

    "Foster, D.L., Nagatani, S., Bucholtz, D.B., Tsukamura, H., Tanaka, T., and Maeda, K.-I( EDITOR:Hansel, W., G. Bray, and D. Ryan)"( Role: Joint author)

    LSU Press  1998 

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    "Links between nutrition and reproduction: signals, sensors and pathways controlling GnRH secretion."

  74. Estrogen feedback actions controlling the responses of hypothalamo-pituitary-gonadal axis to external stimuli in female rats.

    Neural Control of Reproduction : Physiology and Behavior  1997 

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  75. 飢餓ストレスと生殖機能

    前多敬一郎・束村博子( Role: Joint author)

    運動生化学  1997 

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  76. Positive feedback mechanism of estrogen in the arcuate nucleus

    Tsukahara, S., Tsukamura, H. and Maeda, K.-I.( Role: Joint author)

    In Reproductive Biology Update  1997 

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  77. Neural Control of Reproduction. Physiology and Behavior

    "Maeda, K.-I. and Tsukamura, H.( EDITOR:Maeda, K.-I., Tsukamura, H. and Yokoyama, A.)"( Role: Joint author)

    Japan Scientific Society Press/Karger  1997 

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    Estrogen feedback actions controlling the response of hypothalamo-pituitary-gonadal axis to external simuli in female rats

  78. 無拘束・無麻酔のラットを用いた連続採血法

    束村博子・前多敬一郎( Role: Joint author)

    日本比較内分泌学ニュース  1997 

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  79. Novel estrogen feedback sites associated with stress-induced suppression of luteinizing hormone secretion in female rats

    Maeda, K.-I., Nagatani, S., Maria A. Estacio and Hiroko Tsukamura( Role: Joint author)

    Cellular and Molecular Neurobiology  1996 

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  80. 黄体形成ホルモンのパルス状分泌を制御する中枢機構

    束村博子・前多敬一郎( Role: Joint author)

    日本比較内分泌学会ニュース  1996 

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  81. ストレスと生殖をめぐる神経内分泌機構

    束村博子( Role: Sole author)

    ヒューマンサイエンス  1996 

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  82. Neuroendocrine mechanism mediating fasting-induced suppression of luteinizing hormone secretion in female rats

    Maeda, K.-I. and Tsukamura, H.( Role: Joint author)

    Acta Neurobiologiae Experimentalis  1996 

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    Language:English

  83. 生殖機能を制御する脳内メカニズム:GnRH Pulse Generator

    前多敬一郎・大蔵聡・束村博子( Role: Joint author)

    獣医畜産新報  1996 

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    Language:Japanese

  84. ストレス反応を媒介する神経内分泌機構

    前多敬一郎・長谷祥治・束村博子( Role: Joint author)

    第39回プリマーテス研究会報告  1995 

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    Language:Japanese

  85. 黄体形成ホルモンのパルス状分泌を制御する中枢機構

    束村博子( Role: Sole author)

    1995 

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    Language:Japanese

  86. The LHRH pulse generator: A mediobasal hypothalamic location

    Maeda, K.-I., Tsukamura, H., Ohkura, S. and Yokoyama, A.( Role: Joint author)

    Neuroscience and Biobehavioral Reviews  1995 

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    Language:English

  87. Neuroendocrine mechanism regulating the pulsatile luteinizing hormone secretion.

    Brain Control of the Reproductive System.  1992 

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    Language:English

  88. 生殖機能の環境による調節 -その神経内分泌学的機序

    束村博子・前多敬一郎( Role: Joint author)

    日本畜産学会報  1992 

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    Language:Japanese

  89. ラットにおける無拘束無麻酔下採血のためのカニューレ装着法の実際

    前多敬一郎・束村博子( Role: Joint author)

    アニテックス  1988 

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    Language:Japanese

  90. 泌乳中に排卵しないのはなぜか?

    前多敬一郎・束村博子・横山昭( Role: Joint author)

    生物物理  1987 

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    Language:Japanese

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MISC 13

  1. GPR75シグナリングは摂食を促進的に制御し高脂肪食による過食・肥満・高血糖・インスリン抵抗性を仲介する

    大塚 裕記, 平林 真澄, 井上 直子, 束村 博子, 上野山 賀久

    日本畜産学会大会講演要旨集   Vol. 130回   page: 82 - 82   2022.9

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    Language:Japanese   Publisher:(公社)日本畜産学会  

  2. Kiss1細胞常時可視化遺伝子改変ラットを用いた雌雄脳内Kiss1細胞分布の経時的解析

    山田 晃煕, 長江 麻佑子, 眞野 哲也, 井上 直子, 上野山 賀久, 平林 真澄, 束村 博子

    日本内分泌学会雑誌   Vol. 97 ( 5 ) page: 1348 - 1348   2022.3

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    Language:Japanese   Publisher:(一社)日本内分泌学会  

  3. 室傍核ダイノルフィンニューロンは泌乳ラットにおけるLHパルスの抑制を仲介する

    土田 仁美, 井上 直子, 上野山 賀久, 束村 博子

    日本内分泌学会雑誌   Vol. 97 ( 5 ) page: 1349 - 1349   2022.3

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  4. ほ乳類の生殖を制御する神経内分泌メカニズム

    束村 博子

    日本内分泌学会雑誌   Vol. 97 ( 5 ) page: 1228 - 1228   2022.3

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  5. ATP-プリン受容体シグナリングによるAVPVキスペプチンニューロン由来不死化細胞株活性化の検討

    土肥 由莉, 上野山 賀久, 束村 博子, 井上 直子

    The Journal of Reproduction and Development   Vol. 66 ( Suppl. ) page: j47 - j47   2020.9

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    Language:Japanese   Publisher:(公社)日本繁殖生物学会  

  6. 低栄養による生殖機能抑制は室傍核ダイノルフィンニューロンによる弓状核キスペプチンニューロンの抑制によって仲介される

    土田 仁美, 井上 直子, 上野山 賀久, 束村 博子

    The Journal of Reproduction and Development   Vol. 66 ( Suppl. ) page: j46 - j46   2020.9

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  7. シバヤギにおけるGnRHパルス発生中枢の制御に関わるセロトニン受容体サブタイプの検討

    鈴村 玲香, 森田 康広, 松山 秀一, 佐々木 拓弥, 北川 悠梨, 井上 直子, 上野山 賀久, 束村 博子, 大蔵 聡

    The Journal of Reproduction and Development   Vol. 66 ( Suppl. ) page: j46 - j46   2020.9

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    Language:Japanese   Publisher:(公社)日本繁殖生物学会  

  8. Kiss1発現を制御するエストロジェン受容体αコリプレッサーの探索

    宮崎 紗衣, 井上 直子, 束村 博子, 上野山 賀久

    The Journal of Reproduction and Development   Vol. 66 ( Suppl. ) page: j47 - j47   2020.9

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    Language:Japanese   Publisher:(公社)日本繁殖生物学会  

  9. Kisspeptin・生殖内分泌 哺乳類の排卵を制御する脳内メカニズム

    井上 直子, 上野山 賀久, 束村 博子

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1439 - 1439   2020.2

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  10. 視床下部室傍核ダイノルフィンAニューロンが低栄養による黄体形成ホルモン分泌抑制を仲介する

    土田 仁美, 井上 直子, 上野山 賀久, 束村 博子

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1546 - 1546   2020.2

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  11. 栄養状態が性成熟の到来を制御するメカニズムの解明

    上野山 賀久, Majarune Sutisa, Nima Pelden, 井上 直子, 束村 博子

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1447 - 1447   2020.2

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  12. 栄養による生殖機能・血糖・摂食調節を担うエネルギーセンサーと神経経路の同定

    佐藤 真梨萌, 美辺 詩織, 渡辺 雄貴, 後藤 哲平, 三宝 誠, 平林 真澄, 井上 直子, 上野山 賀久, 真方 文絵, 束村 博子, 松田 二子

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1448 - 1448   2020.2

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  13. 前多敬一郎が遺した教育者・研究者としての使命とビジョン

    束村 博子

    日本内分泌学会雑誌   Vol. 95 ( 4 ) page: 1434 - 1434   2020.2

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Presentations 465

  1. 泌乳後期ラットにおけるKNDyニューロン抑制を担うエストロゲン受容体・共役コリプレッサーの発現解析

    滝沢麻里奈、井上直子、上野山賀久、束村博子

    第27回日本生殖内分泌学会  2022.12  日本生殖内分泌学会

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    Event date: 2022.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:広島   Country:Japan  

  2. GPR75ノックアウトラットは高脂肪食による過食・肥満・糖代謝異常を示さない

    大塚裕記、平林真澄、井上直子、束村博子、上野山賀久

    第1 7回 GPCR 研究会  2022.11  GPCR 研究会

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    Event date: 2022.11

    Language:Japanese   Presentation type:Poster presentation  

    Venue:茨城   Country:Japan  

  3. 新規遺伝子改変動物Kiss1-Creラットを用いた生殖中枢キスペプチンニューロン分布の性差および発達による変化の組織学的解析

    山田晃熙,眞野哲也,長江麻佑子,井上直子,上野山賀久,平林真澄, 束村博子

    第48回日本神経内分泌学会学術集会  2022.10  日本神経内分泌学会

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    Event date: 2022.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:栃木   Country:Japan  

  4. κ-オピオイド受容体発現細胞特異的およびKiss1発現細胞特異的Kiss1ノックアウトラットの生殖機能解析

    長江麻佑子、榎本悠希、米谷麻里、山田晃熙、土田仁美、平林真澄、井上直子、上野山賀久、束村博子

    第46回日本比較内分泌学会大会及びシンポジウム 東京大会  2022.10  日本比較内分泌学会大会

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    Event date: 2022.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  5. キスペプチンニューロン常時可視化ラットを用いた雌雄ラット脳の組織学的解析

    眞野哲也、山田晃煕、長江麻佑子、井上直子、上野山賀久、平林真澄、束村博子

    第46回日本比較内分泌学会大会及びシンポジウム  2022.10  日本比較内分泌学会

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    Event date: 2022.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  6. ATP-P2X2 receptor signaling is essential for the generation of GnRH/LH surgevia activation of kisspeptin neurons in the anteroventral periventricular nucleus

    Hazim Safiullah, Ryoya Yabushita, Mayuko Nagae, Masumi Hirabayashi, Yoshihisa Uenoyama, Hiroko Tsukamura, Naoko Inoue

    2022.10 

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    Event date: 2022.10

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  7. κ-オピオイド受容体発現細胞特異的Kiss1ノックアウト雌ラットの生殖機能解析

    長江 麻佑子,榎本 悠希,米谷 麻里,平林 真澄,井上 直子,上野山 賀久,束村 博子

    第115回 日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京   Country:Japan  

  8. 泌乳ラットのLH分泌抑制および摂食亢進を担うオピオイドシグナリングの役割

    野々垣 弥玖,土田 仁美,井上 直子,束村 博子,上野山 賀久

    第115回日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  9. 性成熟を制御するエストロジェン作用機序の解明を目指したKNDyニューロンにおけるERαコリプレッサーNcor2発現解析

    松永菜央、井上直子、束村博子、上野山賀久

    第115回日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京   Country:Japan  

  10. 室傍核エンケファリンニューロンがグルコース利用阻害によるLH分泌抑制/糖新生を仲介する

    土田仁美、井上直子、上野山賀久、束村博子

    第115回日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  11. エストロジェンが雌ラット視床下部ダイノルフィンニューロンの活性化に及ぼす影響

    藪下 怜也,Safiullah HAZIM,束村 博子,上野山 賀久,井上 直子

    第115回日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:東京   Country:Japan  

  12. キスペプチンニューロンを蛍光により常時可視化したラットを用いた雌雄脳内の蛍光標識細胞分布の経時的解析

    山田晃熙、長江麻佑子、眞野哲也、井上直子、上野山賀久、平林真澄、束村博子

    第115回 日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京   Country:Japan  

  13. 泌乳ラットにおけるエストロゲン依存性のKiss1発現抑制におけるエストロゲン受容体共役コリプレッサーの機能解析

    滝沢麻里奈、井上直子、上野山賀久、束村博子

    第115回 日本繁殖生物学会大会  2022.9  日本繁殖生物学会

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    Event date: 2022.9

    Language:Japanese  

    Venue:東京   Country:Japan  

  14. GPR75シグナリングは摂食を促進的に制御し高脂肪食による過食・肥満・高血糖・インスリン抵抗性を仲介する

    大塚裕記、平林真澄、井上直子、束村博子、上野山賀久

    日本畜産学会第130回大会  2022.9  日本畜産学会

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    Event date: 2022.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB   Country:Japan  

  15. KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator

    Mayuko Nagae, Yoshihisa Uenoyama, Hitomi Tsuchida, Masumi Hirabayashi, Naoko Inoue, Hiroko Tsukamura

    The international congress of neuroendocrinology (ICN 2022)   2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Country:United Kingdom  

  16. Histological analysis of visualized Kiss1 neurons using newly generated Kiss1-Cre rats

    ICN 2022  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Country:United Kingdom  

  17. Involvement of central dynorphin and β-endorphin signaling in glucoprivic LH pulse suppression and gluconeogenesis/feeding International conference

    Hitomi TSUCHIDA、Naoko INOUE、Yoshihisa UENOYAMA、Hiroko TSUKAMUTA

    Kisspeptin 2022  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Country:United Kingdom  

  18. Involvement of central dynorphin and β-endorphin signaling in glucoprivic LH pulse suppression and gluconeogenesis/feeding

    Hitomi TSUCHIDA、Naoko INOUE、Yoshihisa UENOYAMA、Hiroko TSUKAMUTA

    ICN2022  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Country:United Kingdom  

  19. Histological analysis of visualized Kiss1 neurons using newly generated Kiss1-Cre rats

    Koki Yamada, Mayuko Nagae, Tetsuya Mano, Naoko Inoue, Yoshihisa Uenoyama, Masumi Hirabayashi, Hiroko Tsukamura

    Kisspeptin 2022  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Country:United Kingdom  

  20. KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator International conference

    Mayuko Nagae, Yoshihisa Uenoyama, Hitomi Tsuchida, Masumi Hirabayashi, Naoko Inoue, Hiroko Tsukamura

    Kisspeptin 2022  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Poster presentation  

    Venue:グラスゴー   Country:United Kingdom  

  21. KNDy neurones and GnRH/LH pulse generation. Invited International conference

    Hiroko Tsukamura, Yoshihisa UENOYAMA.

    ICN2022  2022.8  ICN

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    Event date: 2022.8

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:2022/8   Country:United Kingdom  

  22. KNDy neurons: the gonadotropin-releasing hormone (GnRH) pulse generator in mammals Invited International conference

    Uenoyama Y, Inoue N, Tsukamura H.

    19thAAAP  2022.8 

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    Event date: 2022.8

    Language:English   Presentation type:Oral presentation (invited, special)  

    Venue:Jeju, Koria.   Country:Korea, Republic of  

  23. DOHaD theory、胎児プログラミングを基軸とする環境内分泌学研究 発達期環境ストレスによる生殖機能不全をもたらす神経内分泌メカニズム Invited

    美辺 詩織, 岩田 衣世, 渡辺 雄貴, 石井 寛高, 井上 直子, 上野山 賀久, 束村 博子, 小澤 一史

    日本内分泌学会第 40 回内分泌代謝学サマーセミナー 2022  2022.7.7  日本内分泌学会

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    Event date: 2022.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:群馬県   Country:Japan  

  24. 哺乳類の卵胞発育を制御する脳内メカニズムの解明

    長江麻佑子、土田仁美、井上直子、束村博子、上野山賀久

    令和3年度日本学術振興会育志賞研究発表会  2022.3.2  日本学術振興会

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    Event date: 2022.3

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  25. 室傍核ダイノルフィンニューロンは泌乳ラットにおけるLHパルスの抑制を仲介する

    土田仁美, 井上直子, 上野山賀久, 束村博子

    第26回日本生殖内分泌学会学術集会  2022.1  日本生殖内分泌学会

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    Event date: 2022.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:石川   Country:Japan  

  26. Kiss1細胞常時可視化遺伝子改変ラットを用いた雌雄脳内Kiss1細胞分布の経時的解析 *全発表者名

    山田晃熙、長江麻佑子、眞野哲也、井上直子、上野山賀久、平林真澄、束村博

    第26回日本生殖内分泌学会学術集会  2022.1.8  日本生殖内分泌学会

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    Event date: 2022.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:石川   Country:Japan  

  27. The Neural Pathway Mediating the Suppression of Reproductive Function during Lactation

    2022.1.7  WEB開催

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    Event date: 2022.1

    Language:English   Presentation type:Poster presentation  

    Country:Japan  

  28. 遺伝子改変ラットを用いた哺乳類の卵胞発育中枢の同定

    長江麻佑子、土田仁美、井上直子、束村博子、上野山賀久

    愛知県農学系4機関による研究交流会  2021.12.17  愛知県農学系4機関

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    Event date: 2021.12

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  29. β-エンドルフィン-µオピオイド受容体シグナリングは低栄養による生殖機能抑制と糖新生/摂食の誘起を仲介する

    土田仁美, 井上直子, 上野山賀久, 束村博子

    第16回 GPCR研究会  2021.11  GPCR研究会

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    Event date: 2021.11

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  30. GPR75シグナリングは高脂肪食による過食・肥満・糖代謝異常を仲介する

    大塚裕記, 平林真澄, 井上直子, 束村博子, 上野山賀久

    第16回 GPCR研究会  2021.11  GPCR研究会

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    Event date: 2021.11

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  31. 卵胞発育を司るGnRHパルス発生機構の同定

    長江麻佑子、土田仁美、井上直子、束村博子、上野山賀久

    第45回日本比較内分泌学会  2021.11  日本比較内分泌学会

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    Event date: 2021.11 - 2021.12

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  32. 脳内β-エンドルフィン-µオピオイド受容体シグナリングがグルコース利用阻害によるLH分泌抑制/糖新生/摂食誘起を仲介する

    土田仁美, 井上直子, 上野山賀久, 束村博子

    第45回日本比較内分泌学会  2021.11  日本比較内分泌学会

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    Event date: 2021.11

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  33. 性成熟を制御する弓状核KNDyニューロン Invited

    上野山賀久、井上直子、束村博子

    第54回日本小児内分泌学会学術集会@札幌コンベンションセンター  2021.10  日本小児内分泌学会

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    Event date: 2021.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:札幌(WEB参加)   Country:Japan  

  34. ほ乳類の生殖を制御する神経内分泌メカニズム Invited

    束村博子

    第47回日本神経内分泌学会学術集会  2021.10  日本神経内分泌学会

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    Event date: 2021.10

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:奈良   Country:Japan  

  35. アデノ随伴ウイルスベクターを用いた効率的なTfap2c-T2A-tdTomatoノックインラットの作製

    長江麻佑子、及川真実、上野山賀久、平林真澄、小林俊寛

    第11回名古屋大学医学系研究科・生理学研究所合同シンポジウム  2021.9.25  名古屋大学医学系研究科

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB開催   Country:Japan  

  36. 室傍核ダイノルフィンAニューロンは泌乳ラットにおけるLHパルス抑制を仲介する

    土田仁美, 井上直子, 上野山賀久, 束村博子

    第114回日本繁殖生物学会大会  2021.9  日本繁殖生物学会

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB開催   Country:Japan  

  37. Search for purinergic neurons projecting to the vicinity of the kisspeptin neurons in the anteroventral periventricular nucleus by retrograde tracing

    Safiullah HAZIM, Yoshihisa UENOYAMA, Hiroko TSUKAMURA, Naoko INOUE

    2021.9 

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    Event date: 2021.9

    Language:English   Presentation type:Oral presentation (general)  

    Country:Japan  

  38. 泌乳ラットにおけるKiss1発現抑制を担うエストロゲン受容体共役コリプレッサーの探索

    滝沢麻里奈, 井上直子, 上野山賀久, 束村博子

    第114回日本繁殖生物学会大会  2021.9  日本繁殖生物学会

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB開催   Country:Japan  

  39. 雌ラットキスペプチンニューロンにおけるSNAP-25遺伝子の発現解析

    山田晃熙、井上直子、上野山賀久、束村博子

    第114回日本繁殖生物学会大会  2021.9  日本繁殖生物学会

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    Event date: 2021.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  40. GnRH パルスジェネレーター解析のための新規 Cre 発現ラットの作製

    長江麻佑子、小林俊寛、三宝誠、平林真澄、水野直彬、中内啓光、榎本悠希、井上直子、束村博子、上野山賀久

    第114回日本繁殖生物学会大会  2021.9  日本繁殖生物学会

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    Event date: 2021.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:WEB開催   Country:Japan  

  41. 生殖の神経内分泌学 Invited

    束村博子

    第35回下垂体研究会学術集会  2021.8  下垂体研究会

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    Event date: 2021.8

    Language:Japanese   Presentation type:Oral presentation (keynote)  

    Venue:福岡   Country:Japan  

  42. 脳は生殖の司令塔/ 畜産物の安定供給のために科学ができること

    束村博子

    GTRセミナー  2021.6  名古屋大学

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    Event date: 2021.6

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋   Country:Japan  

  43. β-エンドルフィン-μ-オピオイド受容体シグナリングはグルコース利用阻害による生殖機能抑制を仲介する

    土田仁美, 河合成美、井上直子, 上野山賀久, 束村博子

    第94回日本内分泌学会学術総会  2021.4  日本内分泌学会

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    Event date: 2021.4

    Language:Japanese   Presentation type:Poster presentation  

    Venue:WEB開催   Country:Japan  

  44. Neuroendocrine mechanism involved in suppression of KNDy neurons/GnRH pulses during malnutrition and lactation Invited International conference

    Hiroko TSUKAMURA

    Kisspeptin Virtual Conference  2021.4 

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    Event date: 2021.4

    Language:English   Presentation type:Oral presentation (invited, special)  

  45. Generation of Genetically Modified Rats for Analysis of Neural Mechanism Involved in GnRH Pulse Generation.

    Mayuko Nagae, Toshihiro Kobayashi, Makoto Sanbo, Masumi Hirabayashi, Naoko Inoue, Hiroko Tsukamura, Yoshihisa Uenoyama

    2021.1.8 

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    Event date: 2021.1

    Language:English   Presentation type:Poster presentation  

  46. 室傍核ダイノルフィンニューロンがグルコース利用阻害による生殖機能抑制を仲介する

    土田 仁美,井上 直子,上野山 賀久,束村 博子

    第25回日本生殖内分泌学会  2020.12  日本生殖内分泌学会

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    Event date: 2020.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  47. 室傍核ダイノルフィンニューロンがグルコース利用阻害による生殖機能抑制を仲介する

    土田 仁美,井上 直子,上野山 賀久,束村 博子

    第25回日本生殖内分泌学会  日本生殖内分泌学会

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    Event date: 2020.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  48. 弓状核特異的Kiss1レスキュー/ノックアウトラットを用いたGnRHパルスジェネレーターの同定

    長江麻佑子、上野山賀久、岡本沙季、土田仁美、池上花奈、後藤哲平、三宝誠、平林真澄、小林憲太、井上直子、束村博子

    第25回日本生殖内分泌学会  日本生殖内分泌学会

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    Event date: 2020.12

    Language:Japanese   Presentation type:Poster presentation  

  49. ATP-プリン受容体シグナリングによるLHサージ制御機構 ~ATPはキスペプチンニューロン不死化細胞のCa2+を上昇させる~

    土肥由莉、大塚裕記、上野山賀久、束村博子、井上直子

    東海畜産学会 

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    Event date: 2020.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  50. 弓状核Kiss1発現を制御するエストロジェン受容体αコリプレッサーの探索

    宮崎紗衣、井上直子、束村博子、上野山賀久

    東海畜産学会 

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    Event date: 2020.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  51. 低栄養による生殖機能抑制は室傍核ダイノルフィンニューロンによる弓状核キスペプチンニューロンの抑制によって仲介される

    土田 仁美,井上 直子,上野山 賀久,束村 博子

    第113回日本繁殖生物学会 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Poster presentation  

  52. ATP-プリン受容体シグナリングによるAVPVキスペプチンニューロン由来不死化細胞株活性化の検討

    土肥由莉、上野山賀久、束村博子、井上直子

    第113回日本繁殖生物学会 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Poster presentation  

  53. 低栄養による生殖機能抑制は室傍核ダイノルフィンニューロンによる弓状核キスペプチンニューロンの抑制によって仲介される

    土田 仁美,井上 直子,上野山 賀久,束村 博子

    第113回日本繁殖生物学会 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  54. Kiss1発現を制御するエストロジェン受容体αコリプレッサーの探索

    宮崎紗衣、井上直子、束村博子、上野山賀久

    第113回日本繁殖生物学会 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Poster presentation  

  55. 遺伝子改変ラットを用いた卵胞発育中枢の同定

    長江麻佑子、上野山賀久、井上直子、小林憲太、平林真澄、束村博子

    第10回名古屋大学医学系研究科・生理学研究所合同シンポジウム 

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    Event date: 2020.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  56. 排卵中枢キスペプチンニューロンを上位から制御するATP-プリン受容体シグナリングの役割

    井上直子、土田仁美、山田晃煕、土肥由莉、上野山賀久、束村博子

    第24回日本生殖内分泌学会学術集会 

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    Event date: 2020.1

    Language:Japanese   Presentation type:Oral presentation (general)  

  57. 視床下部室傍核ダイノルフィンAニューロンが低栄養による黄体形成ホルモン分泌抑制を仲介する

    土田仁美、井上直子、上野山賀久、束村博子

    第24回日本生殖内分泌学会学術集会 

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    Event date: 2020.1

    Language:Japanese   Presentation type:Oral presentation (general)  

  58. Neonatal exposure to estrogen causes irreversible infertility via specific suppressive action on hypothalamic Kiss1 neurons. Invited International conference

    Minabe, S. and Tsukamura, H.

    International Conference on Advances in Biological Science and Technology 

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    Event date: 2019.12

    Language:English   Presentation type:Oral presentation (invited, special)  

  59. 視床下部室傍核ダイノルフィンA ニューロンは低栄養時の生殖機能抑制を仲介する

    土田仁美、井上直子、上野山賀久、束村博子

    令和元年度 東海畜産学会大会 

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    Event date: 2019.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  60. 低栄養時の生殖機能抑制に室傍核ダイノルフィンAニューロンが関与する

    土田仁美、井上直子、上野山賀久、束村博子

    第44回日本比較内分泌学会大会及びシンポジウム 

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    Event date: 2019.11

    Language:Japanese   Presentation type:Poster presentation  

  61. 哺乳類の生殖機能を制御する脳内メカニズム Invited

    束村博子

    第44回日本比較内分泌学会大会及びシンポジウム 

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    Event date: 2019.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  62. 栄養状態が性成熟の到来を制御するメカニズムの解明

    上野山賀久、Majarune Sutisa、Pelden Nima、井上直子、束村博子

    第46回日本神経内分泌学会学術集会 

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    Event date: 2019.10

    Language:Japanese   Presentation type:Oral presentation (general)  

  63. 栄養による生殖機能・血糖・摂食調節を担うエネルギーセンサーと神経経路の同定

    佐藤真梨萌、美辺詩織、渡辺雄貴、後藤哲平、三宝誠、平林真澄、井上直子、上野山賀久、真方文絵、束村博子、松田二子

    第46回日本神経内分泌学会学術集会 

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    Event date: 2019.10

    Language:Japanese   Presentation type:Oral presentation (general)  

  64. 哺乳類の排卵を制御する脳内メカニズム Invited

    井上直子、上野山賀久、束村博子

    第46回日本神経内分泌学会学術集会 

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    Event date: 2019.10

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  65. 弓状核特異的Kiss1コンディショナルノックアウトラットを用いたGnRHパルスジェネレーターの同定

    長江麻佑子、後藤哲平、余郷享子、三宝誠、平林真澄、小林憲太、井上直子、束村博子、上野山賀久

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  66. パルス状GnRH分泌制御機構におけるカルシトニン受容体の役割

    北川悠梨、佐々木拓哉、森島愛、舘林亮輝、森田康広、松山秀一、井上直子、上野山賀久、束村博子、大蔵聡

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Poster presentation  

  67. Kiss1発現制御候補因子Rbbp7発現に及ぼすエストラジオールの影響

    堀畑慶、井上直子、上野山賀久、前多敬一郎、束村博子

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Poster presentation  

  68. 低栄養時の生殖機能抑制に関わる神経経路は室傍核ダイノルフィンAニューロンを仲介する

    土田仁美、井上直子、上野山賀久、束村博子

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  69. シバヤギのパルス状GnRH分泌制御メカニズムにおけるセロトニンの役割

    佐々木拓哉、森島愛、中西真梨菜、鈴村玲香、舘林亮輝、北川悠梨、森田康広、松山秀一、井上直子、上野山賀久、束村博子、大蔵聡

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  70. 低栄養による性腺刺激ホルモン分泌の抑制を担う神経伝達経路とグルコースセンサーの同定

    佐藤真梨萌、美辺詩織、渡辺雄貴、後藤哲平、三宝誠、平林真澄、真方文絵、束村博子、松田二子

    第112回日本繁殖生物学会大会 

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    Event date: 2019.9

    Language:Japanese   Presentation type:Oral presentation (general)  

  71. グルコース濃度低下時に生理機能を制御する神経伝達経路の探索

    佐藤真梨萌、美辺詩織、真方文絵、束村博子、松田二子

    第37回内分泌代謝学サマーセミナー 

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    Event date: 2019.7

    Language:Japanese   Presentation type:Poster presentation  

  72. エストラジオールによるKiss1発現制御候補因子Rbbp7発現変動の検討

    堀畑慶、井上直子、上野山賀久、前多敬一郎、束村博子

    第37回内分泌代謝学サマーセミナー 

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    Event date: 2019.7

    Language:Japanese   Presentation type:Poster presentation  

  73. 弓状核特異的Kiss1KOラットを用いた卵胞発育中枢の同定

    長江麻佑子、後藤哲平、余郷享子、三宝誠、平林真澄、小林憲太、井上直子、束村博子、上野山賀久

    第37回内分泌代謝学サマーセミナー 

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    Event date: 2019.7

    Language:Japanese   Presentation type:Poster presentation  

  74. GnRHパルス発生中枢制御機構におけるカルシトニン受容体の役割

    北川悠梨、佐々木拓哉、森島愛、舘林亮輝、森田康広、松山秀一、井上直子、上野山賀久、束村博子、大蔵聡

    第37回内分泌代謝学サマーセミナー 

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    Event date: 2019.7

    Language:Japanese   Presentation type:Poster presentation  

  75. 室傍核ダイノルフィンAニューロンは低栄養における生殖機能抑制を仲介する

    土田仁美、井上直子、上野山賀久、束村博子

    第37回内分泌代謝学サマーセミナー 

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    Event date: 2019.7

    Language:Japanese   Presentation type:Poster presentation  

  76. キスペプチンニューロンによる生殖制御メカニズム Kisspeptin neuron as a master regulator of animal reproduction Invited

    束村博子

    第92回日本内分泌学会学術総会 

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    Event date: 2019.5

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

  77. キスペプチン遺伝子発現を制御するヒストン修飾関連因子の探索

    堀畑慶、井上直子、家田菜穂子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子

    第23回日本生殖内分泌学会学術集会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡国際会議場(福岡市)   Country:Japan  

  78. ソマトスタチン-ソマトスタチン受容体2系は泌乳期のパルス状黄体形成ホルモン分泌抑制を仲介する

    杉本有沙、土田仁美、家田菜穂子、井上直子、上野山賀久、束村博子

    第23回日本生殖内分泌学会学術集会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:福岡国際会議場(福岡市)   Country:Japan  

  79. キスペプチン遺伝子発現を制御するヒストン修飾関連因子の探索

    堀畑慶、井上直子、家田菜穂子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子

    第23回日本生殖内分泌学会学術集会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  80. ソマトスタチン-ソマトスタチン受容体2系は泌乳期のパルス状黄体形成ホルモン分泌抑制を仲介する

    杉本有沙、土田仁美、家田菜穂子、井上直子、上野山賀久、束村博子

    第23回日本生殖内分泌学会学術集会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

  81. 低栄養時の生殖機能抑制に視床下部室傍核ダイノルフィンAニューロンが関与する

    土田仁美、河合成美、井上直子、上野山賀久、束村博子

    平成30年度東海畜産学会大会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学農学部   Country:Japan  

  82. 視床下部セロトニン-5-HT2C型受容体シグナリングの生殖機能促進効果

    中西真莉菜、堀畑慶、河合成美、井上直子、上野山賀久、束村博子

    平成30年度東海畜産学会大会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学農学部   Country:Japan  

  83. Kiss1ラット弓状核へのKiss1遺伝子導入によるLHパルスの回復

    岡本沙季、池上花奈、小林憲太、井上直子、前多敬一郎、束村博子、上野山賀久

    平成30年度東海畜産学会大会 

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    Event date: 2018.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学農学部   Country:Japan  

  84. 低栄養による生殖機能抑制における室傍核ダイノルフィンAニューロンの関与の可能性

    土田仁美、河合成美、出浦慎哉、井上直子、上野山賀久、束村博子

    第111回日本繁殖生物学会大会 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:信州大学繊維学部(長野県上田市)   Country:Japan  

  85. ニューロキニンB受容体拮抗剤の経口投与はパルス状LH分泌を抑制する

    佐々木拓哉、園田朋也、大石真也、藤井信孝、森田康広、松山秀一、井上直子、上野山賀久、束村博子、前多敬一郎、松田二子、大蔵聡

    第111回日本繁殖生物学会大会 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:信州大学繊維学部(長野県上田市)   Country:Japan  

  86. 新規なキスペプチン遺伝子(Kiss1)発現制御因子の探索

    堀畑慶、井上直子、家田菜穂子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子

    第111回日本繁殖生物学会大会 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:信州大学繊維学部(長野県上田市)   Country:Japan  

  87. プリン作動性ニューロンの作用部位としてのAVPVキスペプチンニューロンの役割

    高橋あい、石垣蓮、出浦慎哉、上野山賀久、束村博子、井上直子

    第111回日本繁殖生物学会大会 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:信州大学繊維学部(長野県上田市)   Country:Japan  

  88. 弓状核特異的Kiss1KOラットを用いたGnRHパルス発生機構の同定

    長江麻佑子、後藤哲平、余郷享子、三宝誠、平林真澄、小林憲太、井上直子、束村博子、前多敬一郎、上野山賀久

    第111回日本繁殖生物学会大会 

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    Event date: 2018.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:信州大学繊維学部(長野県上田市)   Country:Japan  

  89. 視床下部室傍核(PVN)に局在するダイノフィンAニューロンが低栄養時の黄体形成ホルモン(LH)の分泌抑制に関与する可能性

    土田仁美、河合成美、出浦慎哉、井上直子、上野山賀久、束村博子

    第33回日本下垂体研究会学術集会 

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    Event date: 2018.8

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:国民宿舎桂浜荘(高知市)   Country:Japan  

  90. 前多敬一郎が歩んだ人生:研究者として教育者として。〜特別講演2前多敬一郎先生追悼講演 Invited

    束村博子

    第33回日本下垂体研究会学術集会 

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    Event date: 2018.8

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:国民宿舎桂浜荘(高知市)   Country:Japan  

  91. プリン作動性シグナルによるキスペプチンニューロンを介した排卵制御

    井上直子、石垣蓮、高橋あい、上野山賀久、束村博子

    第36回内分泌代謝学サマーセミナー 

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    Event date: 2018.8

    Language:Japanese   Presentation type:Poster presentation  

    Venue:Active Resorts 宮城蔵王(宮城県)   Country:Japan  

  92. キスペプチン遺伝子発現制御を担うヒストン修飾関連因子の探索

    堀畑慶、井上直子、家田菜穂子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子

    第36回内分泌代謝学サマーセミナー 

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    Event date: 2018.8

    Language:Japanese   Presentation type:Poster presentation  

    Venue:Active Resorts 宮城蔵王(宮城県)   Country:Japan  

  93. 脳内グルコース利用阻害による黄体形成ホルモン(LH)分泌抑制への室傍核ダイノルフィンAニューロンの関与の可能性

    土田仁美、河合成美、出浦慎哉、井上直子、上野山賀久、束村博子

    第36回内分泌代謝学サマーセミナー 

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    Event date: 2018.8

    Language:Japanese   Presentation type:Poster presentation  

    Venue:Active Resorts 宮城蔵王(宮城県)   Country:Japan  

  94. GnRHパルスおよびサージ発生中枢の同定を目的としたKiss1-floxedラットの作出

    長江麻佑子、余郷享子、後藤哲平、三宝誠、平林真澄、井上直子、束村博子、前多敬一郎、上野山賀久

    日本畜産学会第124回大会 

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    Event date: 2018.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:東京大学農学部(弥生キャンパス)   Country:Japan  

  95. The Tracing Study of the Neural Pathway Originating from the Hindbrain Ependymocytes for Regulating Reproductive Functions International conference

    Kei Horihata, Naoko Inoue, Nahoko Ieda, Yoshihisa Uenoyama, Yuta Suetomi, Fuko Matsuda, Kei-ichiro Maeda and Hiroko Tsukamura

    ENDO 2018 

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    Event date: 2018.3

    Language:English   Presentation type:Poster presentation  

    Venue:Chicago   Country:United States  

  96. Establishment of Immortalized Cell Lines Derived from Rat AVPV and ARC Kisspeptin Neurons International conference

    Chikaya Deura, Naoko Inoue, Yoshihisa Uenoyama, Kei-ichiro Maeda and Hiroko Tsukamura

    ENDO 2018 

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    Event date: 2018.3

    Language:English   Presentation type:Poster presentation  

    Venue:Chicago   Country:United States  

  97. 脳内 ATP-プリン受容体を介した排卵中枢制御メカニズム

    石垣蓮・家田菜穂子・上野山賀久・束村博子・井上直子

    平成29年度 東海畜産学会大会 

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    Event date: 2017.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学野依記念学術交流館カンファレンスホール   Country:Japan  

  98. 哺乳類の生殖中枢の制御機構解明に資するラットキスペプチンニューロン不死化細胞株の作出

    堀畑慶・井上直子・家田菜穂子・上野山賀久・末富祐太・松田二子・前多敬一郎・束村博子

    平成29年度 東海畜産学会大会 

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    Event date: 2017.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学野依記念学術交流館カンファレンスホール   Country:Japan  

  99. 卵胞発育中枢および排卵中枢の同定を目的とした Kiss1-floxed ラットの作出

    長江麻佑子・余郷享子・後藤哲平・三宝誠・平林真澄・ 井上直子・束村博子・前多敬一郎・上野山賀久

    平成29年度 東海畜産学会大会 

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    Event date: 2017.12

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:名古屋大学野依記念学術交流館カンファレンスホール   Country:Japan  

  100. 低栄養による哺乳類の生殖機能抑制の脳内メカニズム Invited

    束村博子

    2017年度生命科学系学会合同年次大会 

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    Event date: 2017.12

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:神戸ポートアイランド(兵庫県神戸市)   Country:Japan  

  101. 「内分泌学」のダイナミズム Invited

    束村博子

    日本内分泌学会創立90周年記念式典 

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    Event date: 2017.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:神戸国際展示場(兵庫県神戸市)   Country:Japan  

  102. Suckling-induced changes in TIP39 and somatostatin expressions in the rat brain. International conference

    Alisa Sugimoto, Yoshihisa Uenoyama, Nahoko Ieda, Kana Ikegami, Naoko Inoue and Hiroko Tsukamura

    Society for Neuroscience 

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    Event date: 2017.11

    Language:English   Presentation type:Poster presentation  

    Venue:Washington Convention Center(Washington DC)   Country:United States  

  103. 生命現象をのぞき込む〜試験に出ない?基礎研究の凄みと楽しさ〜 Invited

    束村博子

    第10回形態科学シンポジウム 

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    Event date: 2017.11

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:知恩院 和順会館ホール(京都府京都市)   Country:Japan  

  104. Histological analysis of the possible participation of TIP39 and somatostatin in Kiss1 suppression during lactation. International conference

    Alisa Sugimoto, Yoshihisa Uenoyama, Nohoko Ieda, Kana Ikegami, Naoko Inoue and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  105. Expression of Gpr101, receptor gene for GnRH metabolite, in KNDy neurons in female rats. International conference

    Nahoko Ieda, Shiori Minabe, Kana Ikegami, Youki Watanabe, Alisa Sugimoto, Naoko Inoue, Yoshihisa Uenoyama, Kei-ishiro Maeda and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  106. The effect of administration of ATP into the anteroventral periventricular nucleus on LH secretion in female rats. International conference

    Ren Ishigaki, Nahoko Ieda, Yoshihisa Uenoyama, Hiroko Tsukamura and Naoko Inoue

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  107. Expression of calcitonin receptors in kisspeptin neurons in the arcuate and anteroventral periventicular nuclei in female rats. International conference

    Assadullah Dost, Nahoko Ieda, Naoko Inoue, Yoshihisa Uenoyama and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  108. The laclization of μ-opioid receptor-expressing cells in the female rat brain. International conference

    Narumi Kawai, Nahoko Ieda, Yoshihisa Uenoyama, Naoko Inoue and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  109. The Neural pathway originating form the ependymocytes of the hindbrain to the kisspeptin neurons. International conference

    Chikaya Deura, Naoko Inoue, Kei-ichiro Maeda, Yoshihisa Uenoyama and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  110. Establishment and evaluation of rat kisspeptin neuronal cell lines. International conference

    Kei Horihata, Ai Takahashi, Naoko Inoue, Nahoko Ieda, Yoshihisa Uenoyama, Yuta Suetomi, Fuko Matsuda, Kei-ichiro Maeda and Hiroko Tsukamura

    4th World Congress of Reproductive Biology 

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    Event date: 2017.9

    Language:English   Presentation type:Poster presentation  

    Venue:Okinawa Convention Center (Okinawa, Japan)   Country:Japan  

  111. 哺乳類におけるHPG軸と生殖機能制御

    井上直子、家田菜穂子、上野山賀久、束村博子

    第35回内分泌代謝学サマーセミナー 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:水上館(群馬県利根郡)   Country:Japan  

  112. 雌由来臭覚刺激は雌ラット前腹側室周囲核キスペプチンニューロンを活性化しLH分泌を増強する

    渡辺雄貴、池上花奈、石垣蓮、家田菜穂子、上野山賀久、前多敬一郎、束村博子、井上直子

    第35回内分泌代謝学サマーセミナー 

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    Event date: 2017.7

    Language:Japanese   Presentation type:Poster presentation  

    Venue:水上館(群馬県利根郡)   Country:Japan  

  113. 雌ラットKNDyニューロンにおけるGnRH代謝産物受容体の発現

    家田菜穂子、井上直子、上野山賀久、束村博子

    第14回GPCR研究会 

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    Event date: 2017.5

    Language:Japanese   Presentation type:Poster presentation  

    Venue:日本科学未来館(東京都)   Country:Japan  

  114. 生殖を制御する中枢メカニズム:キスペプチンとその発現のエピジェネティック機構 Invited

    束村博子

    第90回日本内分泌学会学術総会 

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    Event date: 2017.4

    Language:English   Presentation type:Oral presentation (general)  

    Venue:京都府京都市   Country:Japan  

  115. Development/Sex Differences of Kiss1 neurons. Invited International conference

    Tsukamura, H.

    3rd World Conference of Kisspeptin-Brain and Beyond 

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    Event date: 2017.3

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Orland, USA   Country:United States  

  116. Involvement of gap junctional communications between KNDy neurons and glial cells in synchronaized discharges of KNDy neurons in mice. International conference

    Kana Ikegami, Nahoko Ieda, Teppei Goto, Alisa Sugimoto, Sho Nakamura, Naoko Inoue, Kei-ichiro Maeda, Hiroko Tsukamura and Yoshihisa Uenoyama

    3rd World Conference of Kisspeptin-Brain and Beyond 

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    Event date: 2017.3

    Language:English   Presentation type:Oral presentation (general)  

    Venue:Orland, USA   Country:Japan  

  117. 前腹側室周囲核へのATPの投与がLH分泌に及ぼす影響

    石垣蓮、家田菜穂子、上野山賀久、束村博子、井上直子

    畜産学会第122回大会 

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    Event date: 2017.3

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:神戸   Country:Japan  

  118. TIP39-ソマトスタチン系による泌乳期キスペプチン遺伝子発現抑制の可能性

    杉本有沙、上野山賀久、渡辺雄貴、家田菜穂子、池上花奈、井上直子、束村博子

    第21回日本生殖内分泌学会学術集会 

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    Event date: 2017.1

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:千里ライフサイエンスセンター(大阪府豊中市)   Country:Japan  

  119. 性成熟期におけるKNDyニューロンの神経ペプチド遺伝子発現におよぼすエストロジェンの影響

    小林卓磨、上野山賀久、家田菜穂子、井上直子、束村博子

    第43回日本神経内分泌学会学術集会 

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    Event date: 2016.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:アクトシティ浜松(静岡県浜松市)   Country:Japan  

  120. ラット脳内におけるμ-オピオイド受容体発現細胞の局在

    河合成美、家田菜穂子、上野山賀久、井上直子、束村博子

    第43回日本神経内分泌学会学術集会 

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    Event date: 2016.10

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:アクトシティ浜松(静岡県浜松市)   Country:Japan  

  121. ラットキスペプチンニューロン不死化細胞株の樹立

    堀畑慶、家田菜穂子、井上直子、上野山賀久、末富祐太、松田二子、前多敬一郎、束村博子

    第109回日本繁殖生物学会大会 

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    Event date: 2016.9

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:麻布大学(神奈川県相模原市)   Country:Japan  

  122. 吸乳刺激による弓状核Kiss1遺伝子発現抑制がTIP39-ソマトスタチンニューロン経路により仲介される可能性

    杉本有沙、上野山賀久、渡辺雄貴、家田菜穂子、池上花奈、井上直子、束村博子

    第109回日本繁殖生物学会大会 

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    Event date: 2016.9

    Language:Japanese   Presentation type:Poster presentation  

    Venue:麻布大学(神奈川県相模原市)   Country:Japan  

  123. Cell-to-cell communication via gap junctions may play a role in gonadotropin-releasing hormone pulse generation. International conference

    Kana Ikegami, Nahoko Ieda, Shiori Minabe, Teppeo Goto, Naoko Inoue, Kei-ichiro Maeda, Hiroko Tsukamura and Yoshihisa Uenoyama

    International Symposium on Pituitary Gland and Related Systems (ISPGRS 2016) 

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    Event date: 2016.9

    Language:English   Presentation type:Poster presentation  

    Venue:Hawaii Imin Internatinal Conference Center, East-West Center, University of Hawaii.   Country:United States  

  124. Establishment of rat kisspeptin neuronal cell lines. International conference

    Kei Horihata, Nahoko Ieda, Noko Inoue, Yoshihisa Uenoyama, Yuta Suetomi, Fuko Matsuda, Kei-ichiro Maeda, Hiroko Tsukamura

    International Symposium on Pituitary Gland and Related Systems (ISPGRS 2016) 

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    Event date: 2016.9

    Language:English   Presentation type:Poster presentation  

    Venue:Hawaii Imin Internatinal Conference Center, East-West Center, University of Hawaii.   Country:United States  

  125. 脳の性分化研究からみる男女共同参画 Invited

    束村博子

    第34回内分泌代謝学サマーセミナー 

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    Event date: 2016.7

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:久山温泉 ホテル夢家(福岡県久山町)   Country:Japan  

  126. 排卵中枢キスペプチンニューロンの性分化には種差がある

    松田二子、渡辺雄貴、大蔵聡、井上直子、上野山賀久、前多敬一郎、束村博子

    第13回GPCR研究会 

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    Event date: 2016.5

    Language:Japanese   Presentation type:Oral presentation (general)  

    Venue:日本科学未来館(東京)   Country:Japan  

  127. 哺乳類の生殖を制御する神経内分泌機構—キスペプチニューロンを中心にー。 Invited

    束村博子

    日本内分泌学会学術総会 

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    Event date: 2016.4

    Language:Japanese   Presentation type:Oral presentation (invited, special)  

    Venue:国立京都国際会館(京都)   Country:Japan  

  128. WCRBの日本開催と日本の家畜繁殖学 Invited

    束村博子

    畜産学会第121回大会 

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    Event date: 2016.3