The analysis of the mechanisms of sleep/wakefulness and feeding behavior regulated by orexin

2005 Fiscal Year Final Research Report Summary

• Project/Area Number: 14104009
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: General pharmacology
• Research Institution: University of Tsukuba
• Principal Investigator: GOTO Katsutoshi University of Tsukuba, Graduate School of Comprehensive Human Sciences, Pharmacology, Professor, 大学院・人間総合科学研究科, 教授 (30012660)
• Co-Investigator(Kenkyū-buntansha): SAKURAI Takeshi University of Tsukuba, Graduate School of Comprehensive Human Sciences, Pharmacology, Associate Professor, 大学院・人間総合科学研究科, 助教授 (60251055) ; YAMANAKA Akihiro University of Tsukuba, Graduate School of Comprehensive Human Sciences, Pharmacology, Assistant Professor, 大学院・人間総合科学研究科, 講師 (60323292)
• Project Period (FY): 2002 – 2005
• Keywords: Orexin / Sleep and wakefulness / Feeding behavior / Transgenic mice / Knockout mice / Slice patch clamp / Neuronal network / Behavioral analysis

Research Abstract

Orexin is a neuropeptide newly identified in 1998. Little had been known about the physiological role of orexin since this peptide was identified as a natural ligand for the orphan G protein coupled receptor by means of "Reverse Pharmacological Strategy". Intracerebroventricular injection of synthesis orexin peptide induced feeding behavior in animals, suggesting that this peptide is involved in the regulation of feeding behavior. Behavioral analysis of the prepro-orexin knockout mice and orexin 2 receptor knockout mice revealed that these mice showed a phenotype strikingly similar to human narcolepsy in the dark period. These results suggest that orexin plays an important role in the regulation of sleep/wakefulness as well as in feeding behavior. To reveal neuronal networks which are involved in the sleep/wakefulness regulation, the afferent to orexin neurons was studied by electrophysiological or histochemical analysis. It was difficult to identify orexin neurons in the living tissue since a small number of orexin neurons are diffusely distributed in the lateral hypothalamic area. To facilitate finding orexin neurons, we made several lines of transgenic mice in which orexin neurons specifically express enhanced green fluorescent protein (EGFP) or retrograde tracer (TTC). Electrophysiological analysis using orexin/EGFP transgenic mice revealed that orexin neurons are inhibited by serotonin and noradrenaline. Histochemical analysis using orexin/GFP::TTC transgenic mice revealed that orexin neurons receive dense innervations from the amygdala and cholinergic neurons in the basal forebrain. In this study, we revealed a neuronal network involved in sleep/wakefulness and feeding behavior.

Research Products

• [Journal Article] Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. (2006)
  • Author(s): Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T
  • Journal Title: J Neurophysiol. (in press)
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cholecystokinin Activates Orexin/Hypocretin Neurons through the Cholecystokinin A Receptor. (2005)
  • Author(s): Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T
  • Journal Title: J Neurosci. 25(32) Pages: 7459-69
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. (2005)
  • Author(s): Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M
  • Journal Title: Neuron 46(2) Pages: 297-308
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Cholecystokinin Activates Orexin/Hypocretin Neurons through the Cholecystokinin A Receptor. (2005)
  • Author(s): Tsujino N, Yamanaka A, Ichiki K, Muraki Y, Kilduff TS, Yagami K, Takahashi S, Goto K, Sakurai T.
  • Journal Title: J Neurosci. 25(32) Pages: 7459-7469
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Input of orexin/hypocretin neurons revealed by a genetically encoded tracer in mice. (2005)
  • Author(s): Sakurai T, Nagata R, Yamanaka A, Kawamura H, Tsujino N, Muraki Y, Kageyama H, Kunita S, Takahashi S, Goto K, Koyama Y, Shioda S, Yanagisawa M.
  • Journal Title: Neuron 46(2) Pages: 297-308
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. (2004)
  • Author(s): Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T
  • Journal Title: J Neurosci. 24(32) Pages: 7159-66
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Serotonergic regulation of the orexin/hypocretin neurons through the 5-HT1A receptor. (2004)
  • Author(s): Muraki Y, Yamanaka A, Tsujino N, Kilduff TS, Goto K, Sakurai T.
  • Journal Title: J Neurosci. 24(32) Pages: 7159-7166
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of orexin neurons by the monoaminergic and cholinergic systems. (2003)
  • Author(s): Yamanaka A, Muraki Y, Tsujino N, Goto K, Sakurai T
  • Journal Title: Biochem Biophys Res Commun. 303(1) Pages: 120-9
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hypothalamic orexin neurons regulate arousal according to energy balance in mice. (2003)
  • Author(s): Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T
  • Journal Title: Neuron 38(5) Pages: 701-13
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hypothalamic orexin neurons regulate arousal according to energy balance in mice. (2003)
  • Author(s): Yamanaka A, Beuckmann CT, Willie JT, Hara J, Tsujino N, Mieda M, Tominaga M, Yagami K, Sugiyama F, Goto K, Yanagisawa M, Sakurai T.
  • Journal Title: Neuron 38(5) Pages: 701-713
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Orexins activate histaminergic neurons via the orexin 2 receptor. (2002)
  • Author(s): Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP, Tominaga M, Goto K, Shioda S, Sakurai T
  • Journal Title: Biochem Biophys Res Commun. 290(4) Pages: 1237-45
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. (2002)
  • Author(s): Moriguchi T, Sakurai T, Takahashi S, Goto K, Yamamoto M
  • Journal Title: J Biol Chem. 277(19) Pages: 16985-92
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways. (2002)
  • Author(s): Zhu Y, Yamanaka A, Kunii K, Tsujino N, Goto K, Sakurai T
  • Journal Title: Physiol Behav. 77(2-3) Pages: 251-7
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Orexins activate histaminergic neurons via the orexin 2 receptor. (2002)
  • Author(s): Yamanaka A, Tsujino N, Funahashi H, Honda K, Guan JL, Wang QP, Tominaga M, Goto K, Shioda S, Sakurai T.
  • Journal Title: Biochem Biophys Res Commun. 290(4) Pages: 1237-1245
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Related Articles, The human prepro-orexin gene regulatory region that activates gene expression in the lateral region and represses it in the medial regions of the hypothalamus. (2002)
  • Author(s): Moriguchi T, Sakurai T, Takahashi S, Goto K, Yamamoto M.
  • Journal Title: J Biol Chem. 277(19) Pages: 16985-16992
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Orexin-mediated feeding behavior involves both leptin-sensitive and -insensitive pathways. (2002)
  • Author(s): Zhu Y, Yamanaka A, Kunii K, Tsujino N, Goto K, Sakurai T.
  • Journal Title: Physiol Behav. 77(2-3) Pages: 251-257
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of orexin neurons by the monoaminergic and cholinergic systems. (2002)
  • Author(s): Yamanaka A, Muraki Y, Tsujino N, Goto K, Sakurai T.
  • Journal Title: Biochem Biophys Res Commun. 303(1) Pages: 120-129
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner.
  • Author(s): Yamanaka A, Muraki Y, Ichiki K, Tsujino N, Kilduff TS, Goto K, Sakurai T.
  • Journal Title: J Neurophysiol. (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] The Orexin/Hypocretin System. (2006)
  • Author(s): Sakurai T, Yamanaka A
  • Total Pages: 359
  • Publisher: Humana Press
  • Description: 「研究成果報告書概要(和文)」より