Role of small GTPase signaling in the direct pathway of basal ganglia

• Project/Area Number: 18K06535
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 46030:Function of nervous system-related
• Research Institution: National Institute for Physiological Sciences
• Principal Investigator: Kobayashi Kenta 生理学研究所, 行動・代謝分子解析センター, 准教授 (70315662)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: Small GTPase / PKA / 大脳基底核 / 線条体 / 直接路 / AAVベクター / Cre/loxPシステム / 運動 / protein kinase A / small GTPase / 大脳基底核ループ / ウイルスベクター

Outline of Final Research Achievements

The basal ganglia regulate important neural functions such as motor control and reward. The direct pathway, which is derived from dopamine D1 receptor-positive neurons in the striatum and projects to the substantia nigra pars compacta, plays an important role in the motor onset and reinforcement. However, the molecular mechanism underlying these neural functions remains unknown. In this study, we succeeded in producing genetically modified mice, in which PKA functioning upstream of small GTPase Rap1 is specifically activated in the direct pathway. These mice exhibited the characteristic behavioral and electrophysiological phenotypes, suggesting the involvement of the PKA signaling in the motor control.

Academic Significance and Societal Importance of the Research Achievements

本研究は、１） 独自に開発したウイルスベクターシステムを駆使して、特定の神経細胞集団における遺伝子の発現誘導を可能にした、２）直接路が司る運動制御の分子基盤を解明した、という点において、学術的な意義は大きいと考えられる。また、本研究で作製された直接路特異的にPKAシグナル伝達系が活性化された遺伝子改変マウスは、直接路の活動性亢進に起因する運動過多症状を示すジストニアの新たなモデル動物となり得る。このモデル動物は、ジストニアの新しい治療法や薬品の開発に大きく貢献する可能性がある。

Research Products

• [Int'l Joint Research] IST Austria(オーストリア)
• [Int'l Joint Research] KU Leuven Medical School(ベルギー)
• [Int'l Joint Research] Chulalongkorn University(タイ)
• [Int'l Joint Research] The University of Sheffield(英国)
• [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] Ventro-dorsal hippocampal pathway gates novelty-induced contextual memory formation (2020)
  • Author(s): Fredes F, Silva MA, Koppensteiner P, Kobayashi K, Joesch M, Shigemoto R
  • Journal Title: Curr Biol Volume: 31 Issue: 1 Pages: 25-38
  • DOI: 10.1016/j.cub.2020.09.074
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Anatomical and electrophysiological analysis of cholinergic inputs from the parabigeminal nucleus to the superficial superior colliculus (2020)
  • Author(s): Tokuoka Kota、Kasai Masatoshi、Kobayashi Kenta、Isa Tadashi
  • Journal Title: Journal of Neurophysiology Volume: 124 Issue: 6 Pages: 1968-1985
  • DOI: 10.1152/jn.00148.2020
  • Peer Reviewed
• [Journal Article] Selective Mesoaccumbal Pathway Inactivation Affects Motivation but Not Reinforcement-Based Learning in Macaques (2020)
  • Author(s): Vancraeyenest Pascaline、Arsenault John T.、Li Xiaolian、Zhu Qi、Kobayashi Kenta、Isa Kaoru、Isa Tadashi、Vanduffel Wim
  • Journal Title: Neuron Volume: 108 Issue: 3 Pages: 568-581
  • DOI: 10.1016/j.neuron.2020.07.013
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct CCK-positive SFO neurons are involved in persistent or transient suppression of water intake (2020)
  • Author(s): Matsuda Takashi、Hiyama Takeshi Y.、Kobayashi Kenta、Kobayashi Kazuto、Noda Masaharu
  • Journal Title: Nature Communications Volume: 11 Issue: 1 Pages: 5692-5692
  • DOI: 10.1038/s41467-020-19191-0
  • Peer Reviewed / Open Access
• [Journal Article] Dissecting the Tectal Output Channels for Orienting and Defense Responses (2020)
  • Author(s): Isa Kaoru、Sooksawate Thongchai、Kobayashi Kenta、Kobayashi Kazuto、Redgrave Peter、Isa Tadashi
  • Journal Title: eneuro Volume: 7 Issue: 5 Pages: 0271-0271
  • DOI: 10.1523/eneuro.0271-20.2020
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Retrograde gene transfer into neural pathways mediated by adeno-associated virus (AAV)-AAV receptor interaction (2020)
  • Author(s): Sano H, Kobayashi K, Yoshioka N, Takebayashi H, Nambu A.
  • Journal Title: J Neurosci Methods Volume: 345 Pages: 108887-108887
  • DOI: 10.1016/j.jneumeth.2020.108887
  • Peer Reviewed
• [Journal Article] Forelimb movements evoked by optogenetic stimulation of the macaque motor cortex (2020)
  • Author(s): Watanabe H, Sano H, Chiken S, Kobayashi K, Fukata Y, Fukata M, Mushiake H, Nambu A
  • Journal Title: Nat Commun Volume: 11 Issue: 1 Pages: 3253-3253
  • DOI: 10.1038/s41467-020-16883-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Layer-specific sensory processing impairment in the primary somatosensory cortex after motor cortex infarction (2020)
  • Author(s): Fukui A, Osaki H, Ueta Y, Kobayashi K, Muragaki Y, Kawamata T, Miyata M
  • Journal Title: Sci Rep Volume: 10 Issue: 1 Pages: 3771-3771
  • DOI: 10.1038/s41598-020-60662-7
  • Peer Reviewed / Open Access
• [Journal Article] Motor cortex can directly drive the globus pallidus neurons in a projection neuron type-dependent manner in the rat (2019)
  • Author(s): Karube F, Takahashi S, Kobayashi K, Fujiyama F
  • Journal Title: Elife Volume: 8 Pages: 1-25
  • DOI: 10.7554/elife.49511
  • Peer Reviewed / Open Access
• [Journal Article] Corticobasal ganglia projecting neurons are required for juvenile vocal learning but not for adult vocal plasticity in songbirds (2019)
  • Author(s): Sanchez-Valpuesta M, Suzuki Y, Shibata Y, Toji N, Ji Y, Afrin N, Asogwa CN, Kojima I, Mizuguchi D, Kojima S, Okanoya K, Okado H, Kobayashi K, Wada K
  • Journal Title: Proc Natl Acad Sci U S A Volume: 116 Issue: 45 Pages: 22833-22843
  • DOI: 10.1073/pnas.1913575116
  • NAID: 120006842193
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dynamic Interaction between Cortico-Brainstem Pathways during Training-Induced Recovery in Stroke Model Rats (2019)
  • Author(s): Ishida A, Kobayashi K, Ueda Y, Shimizu T, Tajiri N, Isa T, Hida H
  • Journal Title: J Neurosci Volume: 39 Issue: 37 Pages: 7306-7320
  • DOI: 10.1523/jneurosci.0649-19.2019
  • Peer Reviewed / Open Access
• [Journal Article] Gene delivery to cone photoreceptors by subretinal injection of rAAV2/6 in the mouse retina (2019)
  • Author(s): Hori T, Fukutome M, Maejima C, Matsushima H, Kobayashi K, Kitazawa S, Kitahara R, Kitano K, Kobayashi K, Moritoh S, Koike C
  • Journal Title: Biochem Biophys Res Commun Volume: 515 Issue: 1 Pages: 222-227
  • DOI: 10.1016/j.bbrc.2019.05.117
  • Peer Reviewed / Open Access
• [Journal Article] GABAergic neurons in the olfactory cortex projecting to the lateral hypothalamus in mice (2019)
  • Author(s): Murata K, Kinoshita T, Fukazawa Y, Kobayashi K, Kobayashi K, Miyamichi K, Okuno H, Bito H, Sakurai Y, Yamaguchi M, Mori K, Manabe H
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 7132-7132
  • DOI: 10.1038/s41598-019-43580-1
  • NAID: 120006862679
  • Peer Reviewed / Open Access
• [Journal Article] Impaired cortico-striatal excitatory transmission triggers epilepsy (2019)
  • Author(s): Miyamoto Hiroyuki、Tatsukawa Tetsuya、Shimohata Atsushi、Yamagata Tetsushi、Suzuki Toshimitsu、Amano Kenji、Mazaki Emi、Raveau Matthieu、Ogiwara Ikuo、Oba-Asaka Atsuko、Hensch Takao K.、Itohara Shigeyoshi、Sakimura Kenji、Kobayashi Kenta、Kobayashi Kazuto、Yamakawa Kazuhiro
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 1917-1917
  • DOI: 10.1038/s41467-019-09954-9
  • Peer Reviewed / Open Access
• [Journal Article] Evaluation of AAV-DJ vector for retinal gene therapy (2019)
  • Author(s): Katada Y, Kobayashi K, Tsubota K, Kurihara T
  • Journal Title: PeerJ Volume: 7 Pages: e6317-e6317
  • DOI: 10.7717/peerj.6317
  • Peer Reviewed / Open Access
• [Journal Article] Dissecting the circuit for blindsight to reveal the critical role of pulvinar and superior colliculus (2019)
  • Author(s): Kinoshita M, Kato R, Isa K, Kobayashi K, Kobayashi K, Onoe H, Isa T
  • Journal Title: Nat Commun Volume: 10 Issue: 1 Pages: 135-135
  • DOI: 10.1038/s41467-018-08058-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] [Na+] increases in body fluids sensed by central Nax induce sympathetically mediated blood pressure elevations via H+-dependent activation of ASIC1a. (2019)
  • Author(s): Nomura, K., Hiyama, T.Y., Sakuta, H., Matsuda, T., Lin, C.H., Kobayashi, K., Kobayashi, K., Kuwaki, T., Takahashi, K., Matsui, S., and Noda, M.
  • Journal Title: Neuron Volume: 101 Issue: 1 Pages: 60-75
  • DOI: 10.1016/j.neuron.2018.11.017
  • Peer Reviewed
• [Journal Article] Super-wide-field two-photon imaging with a micro-optical device moving in post-objective space (2018)
  • Author(s): Terada SI, Kobayashi K, Ohkura M, Nakai J, Matsuzaki M
  • Journal Title: Nat Commun Volume: 9 Issue: 1 Pages: 3550-3550
  • DOI: 10.1038/s41467-018-06058-8
  • Peer Reviewed / Open Access
• [Journal Article] Soluble epoxide hydrolase plays a key role in the pathogenesis of Parkinson’s disease (2018)
  • Author(s): Ren Qian、Ma Min、Yang Jun、Nonaka Risa、Yamaguchi Akihiro、Ishikawa Kei-ichi、Kobayashi Kenta、Murayama Shigeo、Hwang Sung Hee、Saiki Shinji、Akamatsu Wado、Hattori Nobutaka、Hammock Bruce D.、Hashimoto Kenji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 25
  • DOI: 10.1073/pnas.1802179115
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Distribution of axon collaterals of ventral tegmental area-cortical motor area projection neurons in rats: a study with double infection of retrograde and anterograde viral vectors (2020)
  • Author(s): Yoshinori Koshimizu, Kenta Kobayashi, Kaoru Isa, Tadashi Isa
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Pyramidal neurons projecting to the globus pallidus and their synaptic targets (2020)
  • Author(s): Fuyuki Karube, Susumu Takahashi, Kenta Kobayashi, Fumino Fujiyama
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Retrospective fear: fearful emotion caused by activation of the efference copy signal for escape behavior from superior colliculus to amygdala (2020)
  • Author(s): Kaoru Isa, Thongchai Sooksawate, Sakura Ikeda, Sara Karimi, Kenta Kobayashi, Tadashi Isa
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Structural dynamics and stability of corticocortical and thalamocortical axon terminals during motor learning (2020)
  • Author(s): Ryota Hasegawa, Teppei Ebina, Yasuhiro R Tanaka, Kenta Kobayashi, Masanori Matsuzaki
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Altered input-side dependent asymmetry of CA3-CA1 synapses lacking PirB expression in pre- or postsynaptic neurons (2020)
  • Author(s): Tsuneyuki Koga, David Kleindienst, Hana Kolinkova, Makoto Sanbo, Kenta Kobayashi, Manabu Abe, Kenji Sakimura, Masumi Hirabayashi, Ryuichi Shigemoto
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Modulation of prefrontal neural network by the optogenetic manipulation of the ventral tegmental area using a novel LED probe device and highly efficient viral vector system (2020)
  • Author(s): Hirotaka Onoe, Kaoru Isa, Reona Yamatuchi, Yoshinori Koshimizu, Sjoerd Murris, Muhammad Zubair, Wim Vanduffel, Kenta Kobayashi, Yasumi Ohta, Takashi Tokuda, Jun Ohta, Tadashi Isa
  • Organizer: The 43rd Annual Meeting of the Japan Neuroscience Society
• [Presentation] Physiological and anatomical organization of cortico-striatal inputs in the basal ganglia (2019)
  • Author(s): Sano H, Kobayashi K, Kato S, Chiken S, Kobayashi K, Nambu A
  • Organizer: The 9th FAOPS Congress
  • Int'l Joint Research
• [Presentation] Dendritic mechanisms underlying perceptual memory consolidation during sleep (2019)
  • Author(s): Daichi Hirai, Daisuke Miyamoto, Yasuhiro Oisi, Maya Odagawa, Chie Matsubara, Kanako Ueno, Kenta Kobayashi, Akiko Hayashi-Takagi, Masanori Murayama
  • Organizer: NEURO2019
• [Presentation] Gene therapy for DRPLA model mice by AAV-delivered CRISPR / Cas9 (2019)
  • Author(s): Taisuke Kato, Yuka Koike, Sachiko Hirokawa, Kenta Kobayashi, Shoji Tsuji, Osamu Onodera
  • Organizer: NEURO2019
• [Presentation] Differential infection pattern of AAVs in mouse retina (2019)
  • Author(s): Masashi Fukutome, Tesshu Hori, Chisato Maejima, Kenta Kobayashi, Satoru Morito, Chieko Koike
  • Organizer: NEURO2019
• [Presentation] Identification of stimulus coding neurons using Cosmoscopy, a new wide-field two-photon microscopy (2019)
  • Author(s): Keisuke Ota, Yasuhiro Oisi, Takayuki Suzuki, Tsubasa Ito, Yoshiki Ito, Kenta Kobayashi, Midori Kobayashi, Maya Odagawa, Chie Matsubara, Junya Matsushita, Hiroyuki Hioki, Masamichi Ohkura, Junichi Nakai, Masafumi Oizumi, Atsushi Miyawaki, Toru Aonishi, Takahiro Ode, Masanori Murayama
  • Organizer: NEURO2019
• [Presentation] Role of the pathway from deeper layer of superior colliculus to amygdala in control of defense-like responses (2019)
  • Author(s): Kaoru Isa, Thongchai Sooksawate, Sakura Ikeda, Kenta Kobayashi, Tadashi Isa
  • Organizer: NEURO2019
• [Presentation] Dynamic interaction between the cortico-rubral and the cortico-reticular tract in rehabilitation-induced functional recovery in internal capsule hemorrhage rats (2019)
  • Author(s): Akimasa Ishida, Kenta Kobayashi, Yoshitomo Ueda, Takeshi Shimizu, Naoki Tajiri, Tadashi Isa, Hideki Hida
  • Organizer: NEURO2019
• [Book] 実験医学別冊 ウイルスベクターによる遺伝子導入実験ガイド (2020)
  • Author(s): 小林憲太
  • Total Pages: 281
  • Publisher: 羊土社
• [Remarks] 生理学研究所 ウィルスベクター開発室
  • URL: https://www.nips.ac.jp/research/group/post-30/