The functional analysis of interneurons in central nervus system.

• Project/Area Number: 12680774
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Neuroscience in general
• Research Institution: KYOTO UNIVERSITY
• Principal Investigator: WATANABE Dai (2001) Kyoto University, Faculty of medicine, Assistant Professor, 医学研究科, 助手 (90303817); 田川 義晃 (2000) 京都大学, 生命科学研究科, 助手 (50303813)
• Co-Investigator(Kenkyū-buntansha): 渡辺 大 京都大学, 医学研究科, 助手 (90303817) ; 金子 鋭 京都大学, 医学研究科, 助手 (70303815)
• Project Period (FY): 2000 – 2001
• Project Status: Completed (Fiscal Year 2001)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,900,000); Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000); Fiscal Year 2000: ¥2,100,000 (Direct Cost: ¥2,100,000)
• Keywords: interneuron / transgenic mouse / immunotoxin / glutamute receptor / adenovirus vector / 受容体

Research Abstract

1. The cellular origin and mechanism of directional selectivity were investigated by selectively eliminating retinal cholinergic interneurons, namely starburst cells, using the immunotoxin-mediated cell targeting techniques (IMCT). Starburst cell ablation in the retina abolished not only directional selectivity of ganglion cell responses but also an optokinetic eye reflex derived by stimulus movement. Starburst cells therefore serve as the key element that discriminates the direction of stimulus movement through integrative synaptic transmission and play a pivotal role in information processing that stabilizes image motion.
2. The physiological role of striatal cholinergic interneurons was investigated with IMCT. Unilateral cholinergic cell ablation caused an acute abnormal turning behavior. These mice showed gradual ecovery but displayed abnormal turning by both excess stimulation and inhibition of dopamine actions. In the acute phase, basal ganglia function was shifted to a hyperactiv e state by stimulation and suppression of striatonigral and striatopallidal neurons, respectively. D1 and D2 dopamine receptors were then down-regulated, relieving dopamine-predominant synaptic perturbation but leaving a defect in controlling dopamine responses.
3. Chronic exposure to cocaine causes long-lasting behavioral changes associated with cocaine reinforcement and addiction. An important neural substrate for cocaine addiction is the nucleus accumbens (Nac). Although the neural circuit of the Nac is controlled by several other neurotransmitters, their involvement in cocaine addiction remains elusive. We ablated cholinergic interneurons from the adult Nac with IMCT and examined the role of acetylcholine transmitter in adaptive behavioral changes associated with cocaine reinforcement and addiction. In bilaterally cholinergic cell-eliminated mice, chronic cocaine administration induced a prominent and progressive increase in locomotor activity. Moreover, these mice showed robust conditioned place preference with a lower dose of cocaine, compared with wild-type littermates. This investigation demonstrates that acetylcholine in the Nac plays a key role in actions of cocaine.

Research Products

• [Publications] Kameko, S., Hikida, T., Watanabe, D., Ichinose, H., Nagatsu, T., Kreitman, R.J., Pastan, I., Nakanishi, S.: "Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function"Science. 289. 633-637 (2000)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hikida, T., Kaneko, S., Isobe, T., Kitabatake, Y., Watanabe, D., Pastan, I., Nakanishi, S.: "Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens"Proc. Natl. Acad. Sci. USA. 98. 13351-13354 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Yoshida, K., Watanabe, D., Ishikane, H., Tachibana, M., Pastan, I., Nakanishi, S.: "A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement"Neuron. 30. 771-780 (2001)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Hazama, M., Watanabe, D., Suzuki, M., Mizoguchi, A., Pastan, I., Nakanishi, S.: "Different regulatory sequences are required for parvalbumin gene expression in skeltal muscles and neuronal cells of transgenic mice"Molecular Brain Research. (in press).
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Kaneko, S., Hikida, T., Watanabe, D., Ichinose, H., Nagatsl, T., Kreitman, R. J., Pastan, I., and Nakanishi, S: "Synaptic integration mediated by striatal cholinergic interneurons in basal ganglia function"Science. 289. 633-637 (2000)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yoshida, K., Watanabe, D., Ishikane, H., Tachibana, M., Pastan, I., and Nakanishi, S.: "A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement."Neuron. 30. 771-780 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hikida, T., Kaneko, S., Isobe, T., Kitabatake, Y., Watanabe D., Pastan, I., and Nakanishi, S.: "Increased sensitivity to cocaine by cholinergic cell ablation nucleus accumbens."Proc Natl Acad Sci U S A. 98. 13351-13354 (2001)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Hazama, M., Watanabe, D., Suzuki, M., Mizoguchi, A., Pastan, I., Nakanishi, S.: "Differerent regulatory sequences are required for parvalbumi gere expression in skeltal muscles and neuronal cells of transgenic mice."Molecular Brain Research. (in press).
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Yoshida, K., Watanabe, D., Ishikane, H., Tachibana, M., Pastan, I., Nakanishi, S.: "A key role of starburst amacrine cells in originating retinal directional selectivity and optokinetic eye movement"Neuron. 30. 771-780 (2001)
• [Publications] Hikida, T., Kaneko, S., Isobe, T., Kitabatake, Y., Watanabe, D., Pastan, I., Nakanishi, S.: "Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens"Proc Natl Acad Sci USA. 98. 13351-13354 (2001)
• [Publications] Hazama, M., Watanabe, D., Suzuki, M., Mizoguchi, A., Pastan, I., Nakanishi, S.: "Diffrerent regulatory sequences are required for parvalbumin gene expression in skeltal muscles and neuronal cells of transgenic mice"Molecular Brain Research. (in press). (2002)
• [Publications] Satoshi Kaneko,Takatoshi Hikida,Dal Watanabe,Hiroshi Ichinose,Toshiharu Nagatsu,Robert J.Kreitman,Ira Pastan,and Shigetada Nakanishi: "Synaptic Integration Mediated by Striatal Cholinergic Interneurons in Basal Ganglia"Science. 289. 633-637 (2000)
• [Publications] Kazumichi Yoshida Dai Watanabe,Hiroshi Ishikane,Masau Tachibana,Ira Pastan and Shigetada Nakanishi: "A Key Role of Starburst Amacrine Cells in Originating Retinal Directional Selectivity and Optokinetic Eye Movement"Neuron. (in press).