Neural circuit basis for the onset of puberty by leptin signaling

• Project/Area Number: 19K16270
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 46010:Neuroscience-general-related
• Research Institution: Institute of Physical and Chemical Research
• Principal Investigator: Goto Teppei 国立研究開発法人理化学研究所, 生命機能科学研究センター, 基礎科学特別研究員 (20772049)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2019: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 性成熟 / キスペプチン / 制限給餌 / レプチン / 逆行性トランスシナプス標識 / トレーシング / 神経回路

Outline of Research at the Start

本研究はレプチン受容して性成熟を惹起する責任ニューロンの同定とそこから生殖中枢に至る神経回路を明らかにすることを目的とする。具体的に、レプチンシグナルを受容する責任ニューロンを全脳レベルでスクリーニング、一細胞レベルの神経接続を可視化できるトランスシナプス標識によってレプチン受容の責任ニューロンから生殖中枢に至る神経回路の構造の解明、さらにレプチン受容の責任ニューロンの神経化学的特性の解明、の3点を試みる。

Outline of Final Research Achievements

The onset of puberty occurs as the body grows. Feeding restriction during the peripubertal period in mice induces failure of puberty onset. When the mice were given free access to food from feeding restriction, body weight increased rapidly, and the mice reached puberty. In vivo calcium imaging from kisspeptin neurons, reproductive center revealed that ad libitum feeding increased the activity of kisspeptin neurons. Supplementation of leptin during feeding restriction had no effect on puberty onset. Thus, a sufficient diet during the peripubertal period enhances the neural activity of kisspeptin neurons. However, the responsible substances for the onset of puberty still need to be studied.

Academic Significance and Societal Importance of the Research Achievements

10代女性のアスリートや極端な食事制限等による急激な体重減少を原因とした思春期の女性における無月経が社会的問題となっている。本研究で確立した制限給餌による性成熟不全モデルはこの思春期女性の無月経を模していると考えられる。性成熟期の制限給餌が脳内キスペプチンニューロン活動を抑制するという知見は、思春期女性の無月経の発生機序の理解に有用であると考えられる。

Research Products

• [Journal Article] Blastocyst complementation using Prdm14-deficient rats enables efficient germline transmission and generation of functional mouse spermatids in rats (2021)
  • Author(s): Toshihiro Kobayashi, Teppei Goto, Mami Oikawa, Makoto Sanbo, Fumika Yoshida, Reiko Terada, Naoko Niizeki, Naoyo Kajitani, Kanako Kazuki, Yasuhiro Kazuki, Shinichi Hochi, Hiromitsu Nakauchi, M. Azim Surani & Masumi Hirabayashi
  • Journal Title: Nature Comminications Volume: 12 Issue: 1 Pages: 13281-10
  • DOI: 10.1038/s41467-021-21557-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct evidence that KNDy neurons maintain gonadotropin pulses and folliculogenesis as the GnRH pulse generator (2021)
  • Author(s): Nagae Mayuko、Uenoyama Yoshihisa、Okamoto Saki、Tsuchida Hitomi、Ikegami Kana、Goto Teppei、Majarune Sutisa、Nakamura Sho、Sanbo Makoto、Hirabayashi Masumi、Kobayashi Kenta、Inoue Naoko、Tsukamura Hiroko
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 118 Issue: 5
  • DOI: 10.1073/pnas.2009156118
  • Peer Reviewed / Open Access
• [Journal Article] Testosterone supplementation rescues spermatogenesis and in vitro fertilizing ability of sperm in Kiss1 knockout mice. (2020)
  • Author(s): T. Goto, M. Hirabayashi, Y. Watanabe, M. Sanbo, K. Tomita, N. Inoue, H. Tsukamura, Y. Uenoyama.
  • Journal Title: Endocrinology Volume: - Issue: 9 Pages: 1-11
  • DOI: 10.1210/endocr/bqaa092
  • Peer Reviewed
• [Journal Article] Conditional Kisspeptin Neuron-Specific Kiss1 Knockout With Newly Generated Kiss1-floxed and Kiss1-Cre Mice Replicates a Hypogonadal Phenotype of Global Kiss1 Knockout Mice (2020)
  • Author(s): 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 Title: J Reprod Dev. Volume: in press Issue: 4 Pages: 359-367
  • DOI: 10.1262/jrd.2020-026
  • NAID: 130007888736
  • Peer Reviewed / Open Access
• [Journal Article] Inducible Kiss1 knockdown in the hypothalamic arcuate nucleus suppressed pulsatile secretion of luteinizing hormone in male mice (2020)
  • Author(s): 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 Title: Journal of Reproduction and Development Volume: Epub Issue: 4 Pages: 369-375
  • DOI: 10.1262/jrd.2019-164
  • NAID: 130007888724
  • Peer Reviewed / Open Access