Using subtractive hybridization, we have isolated a novel neuropeptide gene which is expressed exclusively in a subregion of the posterior hypothalamus. Hypocretin contains a eukaryotic secretory signal sequence and encodes two neuropeptides, 38 and 28 amino acids in length, which are conserved between mouse, rat, and human, indicating an evolutionarily conserved function for these novel neuropeptides. We have raised a high quality antiserum to the hypocretin neuropeptide precursor, localized cell bodies within the hypothalamus, and begun mapping of the terminal projections of hypocretin-containing neurons. We have also obtained evidence that these novel peptides affect neuronal excitability and intracellular calcium levels in vitro and body temperature in vivo. Other investigators have isolated these same molecules which they called the orexins and demonstrated that the affect food intake. Based on these results, we hypothesize that the hypocretin peptides play a role in regulating energy balance and metabolism. We propose to characterize further this novel neurotransmitter pathway by describing the phenotype of neurons which express hypocretin in the hypothalamus and identifying the neuroanatomical regions to which hypocretin-containing neurons project. In in vitro studies, we will characterize the response of neurons to hypocretin peptidergic stimulation and determine the cellular electrophysiological response of neurons to hypocretin application. We will also conduct in vivo studies in which we will obtain functional information about the effects of hypocretin neuropeptides on brain activity and test the hypothesis that hypocretin peptides play a CNS role in regulating energy balance and metabolism. This proposal presents an exciting, integrated research program to characterize a heretofore unstudied neurotransmitter system expressing this novel set of neuropeptides and to determine the effects of these peptides in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH061755-02
Application #
6187034
Study Section
Special Emphasis Panel (ZRG1-IFCN-2 (01))
Program Officer
Winsky, Lois M
Project Start
1999-09-30
Project End
2004-05-31
Budget Start
2000-06-15
Budget End
2001-05-31
Support Year
2
Fiscal Year
2000
Total Cost
$286,311
Indirect Cost
Name
Sri International
Department
Type
DUNS #
City
Menlo Park
State
CA
Country
United States
Zip Code
94025
Hara, Junko; Gerashchenko, Dmitry; Wisor, Jonathan P et al. (2009) Thyrotropin-releasing hormone increases behavioral arousal through modulation of hypocretin/orexin neurons. J Neurosci 29:3705-14
Scammell, Thomas E; Willie, Jon T; Guilleminault, Christian et al. (2009) A consensus definition of cataplexy in mouse models of narcolepsy. Sleep 32:111-6
Matsuki, Taizo; Nomiyama, Mika; Takahira, Hitomi et al. (2009) Selective loss of GABA(B) receptors in orexin-producing neurons results in disrupted sleep/wakefulness architecture. Proc Natl Acad Sci U S A 106:4459-64
Kilduff, Thomas S; Lein, Ed S; de la Iglesia, Horacio et al. (2008) New developments in sleep research: molecular genetics, gene expression, and systems neurobiology. J Neurosci 28:11814-8
Gerashchenko, Dmitry; Wisor, Jonathan P; Burns, Deirdre et al. (2008) Identification of a population of sleep-active cerebral cortex neurons. Proc Natl Acad Sci U S A 105:10227-32
Xie, Xinmin; Wisor, Jonathan P; Hara, Junko et al. (2008) Hypocretin/orexin and nociceptin/orphanin FQ coordinately regulate analgesia in a mouse model of stress-induced analgesia. J Clin Invest 118:2471-81
Yamanaka, Akihiro; Muraki, Yo; Ichiki, Kanako et al. (2006) Orexin neurons are directly and indirectly regulated by catecholamines in a complex manner. J Neurophysiol 96:284-98
Xie, Xinmin; Crowder, Tara L; Yamanaka, Akihiro et al. (2006) GABA(B) receptor-mediated modulation of hypocretin/orexin neurones in mouse hypothalamus. J Physiol 574:399-414
Tsujino, Natsuko; Yamanaka, Akihiro; Ichiki, Kanako et al. (2005) Cholecystokinin activates orexin/hypocretin neurons through the cholecystokinin A receptor. J Neurosci 25:7459-69
Wisor, Jonathan P; Kilduff, Thomas S (2005) Molecular genetic advances in sleep research and their relevance to sleep medicine. Sleep 28:357-67

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